LES RÉGIONS CÉRÉBRALES QUI SE TAISENT OU S'EMBALLENT DURANT LA DÉPRESSION

LES RÉGIONS CÉRÉBRALES QUI SE TAISENT OU S'EMBALLENT DURANT LA DÉPRESSION

Bien que la dépression amène une diminution globale de l’activité cérébrale, il y a certaines régions qui sont particulièrement touchées par cette baisse d’activité.

Ainsi, des études d’imagerie cérébrale avec PET scan ont mis en évidence une activité anormalement basse dans le cortex préfrontal, et plus précisément dans ses parties latérales, orbitofrontales et ventromédianes. La sévérité de la dépression est d’ailleurs souvent reliée au degré de la baisse d’activité du cortex préfrontal.

Celui-ci est non seulement reconnu pour participer à nos réponses émotionnelles, mais aussi pour avoir de nombreuses connexions avec d’autres régions du cerveau responsables du contrôle de la dopamine, de la noradrénaline et de la sérotonine, trois neurotransmetteurs importants pour la régulation de l’humeur. Plus spécifiquement, il semble que le cortex préfrontal latéral nous aide à choisir un comportement en nous permettant d’évaluer mentalement différentes alternatives ; que le cortex orbitofrontal nous permet de réprimer certaines émotions ou gratifications immédiates en vue d’obtenir un avantage encore plus grand à long terme ; et que le cortex ventromédian est un des lieux où les émotions et le sens des choses seraient expérimentés.

1) cortex orbitofrontal 2) cortex préfrontal latéral 3) cortex ventromédian 4) système limbique

Les deux moitiés du cortex préfrontal semblent aussi avoir des fonctions spécialisées, le cortex préfrontal gauche étant impliqué dans l’établissement de sentiments positifs, et le droit dans celui de sentiment négatifs.

Chez les gens en dépression, c’est justement le cortex préfrontal gauche qui montre le plus de signe de faiblesse. En d’autres termes, il devient très difficile pour une personne en dépression de se donner des objectifs en vue d’atteindre une récompense et de croire qu’on peut y parvenir.

Le cortex préfrontal gauche pourrait aussi chez la personne normale contribuer à inhiber les émotions négatives générées par des structures limbiques comme les amygdales qui montrent une activité anormalement élevée chez les patients en dépression. Une activité qui diminue d’ailleurs chez les personnes qui répondent positivement à un traitement aux antidépresseurs. Et lorsque cette hyperactivité de l’amygdale demeure élevée malgré les traitements, elle est alors associée à des fortes possibilités de rechute dans la dépression.

Il est aussi intéressant de noter qu’à un cortex préfrontal gauche fonctionnant à pleine capacité correspond généralement des taux de glucocorticoïdes sanguin très bas. Ce qui en fait un corollaire logique, considérant les effets néfastes des taux élevés de glucocorticoïdes sur l’humeur…

Les études d’imagerie cérébrale ont aussi démontré que les patients atteints de dépressions sévères montrent une diminution du volume de leur deux hippocampes. Cette atrophie pourrait être due à une perte neuronale induite également par l’effet toxique des hauts taux de glucocorticoïdes associés aux épisodes récurrents de dépression.

Il semblerait même que le degré d’atrophie de l’hippocampe soit proportionnel à la somme des durées des épisodes de dépression, et que les dépressions qui sont traitées rapidement n’entraînent pas cette diminution du volume de l’hippocampe (voir les encadrés).

Lors d’une expérience d’imagerie par résonance magnétique fonctionnelle (IRMf), des extraits de films tristes étaient présentés à des sujets normaux et à des sujets en dépression. Chaque groupe devait tenter de réprimer le sentiment de tristesse évoqué par le film. L’image ci-contre représente la différence d'activité cérébrale entre les sujets sains et les sujets en dépression obtenue par soustraction de leur activité respective. Elle montre que les sujets sains ont une activation plus importante de la partie latérale du cortex orbitofrontal (aire de Brodmann 11), une région corticale qui joue un rôle majeur dans la régulation des émotions. Compte tenu que les sujets déprimés éprouvent beaucoup de difficulté à inhiber leur émotions négatives, il n'est pas surprenant d’observer que leur cortex orbitofrontal est moins actif que celui de sujets sains.

Source : Mario Beauregard, Centre de recherche de l'Institut universitaire de gériatrie de Montréal

À la question de savoir pourquoi l’évolution aurait-elle permis l’émergence et le maintient de circuits pouvant amener la dépression, on peut se tourner vers le reste du monde animal pour avoir des pistes de réponses. On peut évoquer bien sûr l’inhibition de l’action qui est observable chez un animal qui ne peut fuir ou lutter contre une situation désagréable et qui s’apparente à la dépression. Le statut des animaux les plus subordonnés dans une hiérarchie pourrait aussi avoir une valeur adaptative en ce qu’elle empêche des combats qui pourraient être très coûteux, voire fatals.

Cela expliquerait aussi pourquoi de nos jours la dépression est souvent initiée par des événements qui minent la confiance en soi d’une personne, l’équivalent d’une défaite face à un animal dominant


Les crises d’épilepsie ayant leur foyer dans le lobe temporal amènent une perte neuronale massive dans l’hippocampe et dans les structures avoisinantes. Or, la dépression est la complication psychiatrique la plus commune chez les patients atteints d’épilepsie, et les patients qui ont leur foyer épileptique dans le lobe temporal sont davantage victimes de dépression que ceux atteints d’autres formes d’épilepsie. Ces observations vont donc tout à fait dans le sens d’un lien entre la dépression et des dommages à l’hippocampe.

	Les troubles anxieux La démence de type Alzheimer

De tous les neurotransmetteurs et hormones qui auraient un rôle à jouer dans la dépression, la sérotonine et les hormones de l’axe hypothalamo-hypophysio-surrénalien sont sans doutes les plus impliquées. Ils partageraient d’ailleurs des voies physiologiques communes qui les garderaient en constante interaction. L’acceptation plus récente que l’hippocampe, une structure du système limbique, fait partie intégrante de l’axe du stress a permis d’avoir une meilleure vue d’ensemble du phénomène complexe de la dépression.

Il devient ainsi de plus en plus évident que l’hyperactivité de l’axe du stress n’est pas qu’un effet secondaire de la dépression. L’axe du stress et le système sérotoninergique interagissent d’ailleurs de plusieurs façons, ce qui n’est sans doute pas étranger au fait que le taux de glucocorticoïdes circulant dans l’organisme affecte grandement notre humeur, en partie à cause de ses effets sur l’hippocampe.

Longtemps associé qu’au traitement cognitif de l’information, et en particulier de la mémoire, l’hippocampe est depuis plus récemment reconnu comme faisant partie intégrante des circuits contrôlant nos humeurs et nos émotions. Le fait que les patients en dépression ont souvent une variété de déficits mnésiques pointe aussi dans la direction d’une implication de l’hippocampe dans la dépression.

about those twisty bacteria known as spirochetes

Spirochetes Unwound

Blogging about those twisty bacteria known as spirochetes

Monday, July 4, 2011

Does Borrelia burgdorferi cause an inadequate antibody response by altering B cell activation in the lymph node?

One of the characteristic features of Lyme disease is lymphadenopathy or swollen lymph nodes.  It's not too surprising when a lymph node draining a site of infection swells.  However when investigators looked at the lymph node draining the inoculation site of Borrelia burgdorferi in mice, they found that the spirochete had somehow altered the course of activation of B cells producing the antibodies that targeted the spirochete.

Before discussing the findings in the paper, a review of how the antibody response evolves in the lymph node is in order.  An antibody response to microbial proteins is sparked when antigen from microbes breaching the skin layer flow into the draining lymph node or are carried to the lymph node by dendritic cells.  Lymph nodes are where naive B cells, upon recognition of antigen, differentiate into plasma cells, which secrete large amounts of antibody that target the invading microbe.  The antibodies which bind most tightly to protein antigens are made with T cell help in germinal centers, which emerge from the rare B cells in the lymph node that produce antibody capable of recognizing the antigen.  (I say "rare" here because each B cell in the lymph node produces antibodies with different antigenic specificities to ensure that any microbe that the host may possibly encounter will be recognized by antibodies displayed by at least a few B cells.)  Upon binding the antigen and reception of critical signals from T cells, the B cells migrate to areas in the lymph node containing fixed networks of follicular dendritic cells (FDCs), a type of immune cell with long branched processes that extend out from the body of the cell.  (FDCs differ from the dendritic cells that bring antigen to the lymph node.)  The B cells then start to proliferate wildly, doubling every 6 to 8 hours (faster than B. burgdorferi!).  As the B cell numbers surge, they form germinal centers, which can be identified easily by standard histological stains (see image below).  The lymph node may even swell, depending on how much the B cells proliferate.

Lymph node: (1) capsule; (2) subcapsular sinus; (3) germinal centers; (4) lymphoide nodule; (5) trabeculae.  Source

As the B cells multiply in the germinal center, a process called somatic hypermutation, which is promoted by signals received from T cells, causes a large number of mistakes to be made within the segment of DNA encoding the antigen binding portion of the antibody.  Consequently, the antibodies displayed by some germinal center B cells are no longer able to bind to the microbial antigen whereas those made by other B cells will bind better.  The FDC processes, whose surfaces are loaded with antigen, continuously probe the antibodies expressed by the newly arising B cells.  Since the new B cells are programmed to die unless they express antibody able to bind the antigen displayed by the FDCs, only B cells displaying antibody that bind most tightly to the antigen will survive.  This process by which B cells expressing the antibodies with the highest affinity for antigen are selected is called affinity maturation.  Somatic hypermutation and affinity maturation can only occur in germinal centers.  The B cells also undergo class switching, in which the class of antibody expressed by the B cells switches from IgM and IgD, which are expressed by naive B cells, to IgA, IgE, or one of the IgG subclasses.  The exact switch that occurs is governed by the cytokines that the B cells are exposed to.  Which cytokines are present depends on the nature of the infection.  Eventually the B cells expressing high-affinity antibodies of the appropriate class differentiate into antibody-secreting plasma cells, which are released from the lymph node to circulate throughout the body and fight the infection.

So what happens in the lymph nodes during a B. burgdorferi infection?  When the investigators inoculated B. burgdorferi into or underneath the skin of mice, the lymph node draining the site swelled considerably, enlarging by more than a factor of 10 by the tenth day of infection.

From Fig. 2 of Tunev et al., 2011.  Arrow points to lymph node draining the inoculation site.  Source

What the investigators saw when they looked at lymph node sections under the microscope was very different from the textbook description of T-cell dependent B cell activation that I gave above.  First of all, live B. burgdorferi was found in the lymph node draining the site of infection in mice.  This is unusual since phagocytes would normally greet and destroy any microbe that managed to find its way into the lymph node.

From Fig. 3 of Tunev et al., 2011.  Day 8 of infection.  The arrows point to intact extracellular B. burgdorferi in the subcapsular sinus of the lymph node, which was culture positive beginning on day 1 of infection.   Source

Second, massive proliferation of B cells accounted for lymph node swelling, but the expansion of B cell numbers wasn't occurring in well-defined germinal centers. The authors also noted that T cells were not increasing in number.  These observations suggested that T cells, which are required for germinal centers to form, were not fully participating in B-cell activation.  The lack of germinal centers suggested that somatic hypermutation and affinity maturation were not occurring.

From their observations, the authors speculated that B. burgdorferi somehow subverted B cell activation in the lymph node so that the end result was a large number of plasma cells secreting antibodies of poor quality.  By poor "quality," I assume that the authors meant that the affinity of the antibody for B. burgdorferi proteins was low and that the "wrong" subclasses of IgG antibodies were expressed.  The most abundant IgG subclasses being produced in the draining lymph node at its most swollen state were IgG2b and IgG3.  Whether other IgG subclasses would be more effective at clearing B. burgdorferi from the host and whether the affinities of the antibodies for B. burgdorferi proteins were poor still need to be determined experimentally.  Perhaps a classic T-cell dependent B cell response involving the formation of germinal centers accompanied by somatic hypermutation, affinity maturation, and appropriate class switching would have led to production of "high" quality antibodies.  If the authors are correct, they have revealed yet another means by which B. burgdorferi could persist in the host.


Featured paper

Tunev SS, Hastey CJ, Hodzic E, Feng S, Barthold SW, and Baumgarth N (May 2011).  Lymphadenopathy during Lyme borreliosis is caused by spirochete migration-induced specific B cell activation.  PLoS Pathogens 7(5):e1002066.  DOI: 10.1371/journal.ppat.1002066

Saturday, June 4, 2011

Membrane fusion between Borrelia spirochetes, a new type of bacterial interaction

It's not unusual for bacteria to collide while swimming around in culture medium.  When this happens, the bacteria simply bounce off each other and swim off in different directions.  However scientists have discovered that the encounter between Borrelia spirochetes, the agents of Lyme disease and relapsing fever, can progress to something more intimate.¹  When they looked at Borrelia cultures under the microscope, the spirochetes that bumped remained stuck to each other side-by-side as they swam.  These encounters were usually brief, lasting for less than 10 seconds, although sometimes they lasted for more than a minute before separating.  If you watch the video below, you'll see two Lyme disease B. afzelii cells near the bottom left corner coming together side-by-side and then separating several seconds later.  The investigators saw similar interactions in cultures of other Lyme disease spirochetes (B. burgdorferi and B. garinii) and a relapsing fever spirochete (B. hermsii).

Movie S2 from Kudryashev et al., 2011

When I first saw the video, I thought that the spirochetes were simply getting tangled up and that it took several seconds for them to get untangled.  However when the investigators examined the cultures by cryoelectron tomography (a type of electron microscopy), they saw that the Borrelia cells weren't merely tangled or stuck to each other.  Their outer membranes were actually fused, sometimes so extensively that both cytoplasmic cylinders ended up in a single outer membrane sheath.  Panel A below shows a cross-section of fused B. garinii cells.  Panel B  shows a 3-dimensional rendering of the the fused spirochetes from panel A.  The two cytoplasmic cylinders (bright and dark magenta) are surrounded by a single outer membrane sheath.  The flagellar filaments from both cells form a single bundle and are shown in yellow.

Figure 4A and 4B from Kudryashev et al., 2011

Artifacts are minimized in specimens observed by cryoelectron tomography because the specimen does not have to be fixed with harsh chemicals.  Instead, the live specimen is placed on an electron microscope grid and plunge-frozen to preserve the structure of the biological sample.  Still, as the authors point out, fusion of Borrelia cells could be an artifact of preparing the spirochetes for cryoelectron tomography.  The outer membrane of Borrelia cells could have fused while collecting the spirochetes by centrifugation or when blotting excess liquid from the electron microscopy grid before freezing the specimen.

Assuming that this was not a preparation artifact, what could be the role of outer membrane fusion in the biology of Borrelia?  The authors present two possibilities.  First, Borrelia cells can share their outer membrane contents by fusing their outer membranes together.  Sharing may be advantageous to Lyme Borrelia during transmission from the tick to the victim's skin, when the spirochetes are turning on genes encoding protective proteins such as OspC.  One can imagine Borrelia cells sharing its protective surface proteins with others that have yet to express them so that a larger number of spirochetes can fend off host defenses and establish an infection.  Another intriguing possibility is that DNA is exchanged between the two spirochetes.  Out of the 110 pairs of fused Borrelia cells observed by cryoelectron tomography, the investigators found one pair whose inner membranes were also fused, providing a conduit (at least theoretically) for transfer of DNA.  Cells in culture may not remain fused long enough to transfer DNA, but Lyme disease Borrelia lie dormant in the tick midgut for months, giving Borrelia cells lying next to each other plenty of time to exchange DNA, assuming that membrane fusion and DNA transfer can even occur in this setting.

The outer membrane of spirochetes is unique among diderm (double-membrane) bacteria because of its loose association with the underlying peptidoglycan layer.  For this reason the outer membrane of all spirochetes, not just those of Borrelia, may be especially prone to fusing.  This raises the possibility that the outer membranes of other spirochetes such as Leptospira and Treponema could also fuse.

Note: This work has also been described in the blog Small Things Considered.

Reference

1. Kudryashev M., Cyrklaff M., Alex B., Lemgruber L, Baumeister W, Wallich R, and Frischknecht F (May 2011).  Evidence of direct cell-cell fusion in Borrelia by cryogenic electron tomography.  Cellular Microbiology 13(5):731-741.  DOI: 10.1111/j.1462-5822.2011.01571.x

Sunday, May 1, 2011

A new attenuated leptospirosis vaccine protects hamsters from lethal infection by more than one serovar of Leptospira

Scientists have demonstrated that a new attenuated leptospirosis vaccine protects laboratory hamsters from being killed by Leptospira, even when the challenge and vaccine strains belong to different serovars (immune types).^1,2  This is the first leptospirosis vaccine to confer complete cross-protection against lethal infection by a serovar different from the one used for immunization.

The leptospirosis vaccines that are out on the market are still formulated with killed Leptospira or sometimes their outer membrane.  These traditional vaccines are administered primarily to dogs, cattle, and pigs.  Human leptospirosis vaccines are not available in most countries, even in areas where leptospirosis is endemic.

New types of leptospirosis vaccines are needed since the traditional killed vaccines are flawed.  One problem is that immunity is serovar specific.  For this reason a vaccine must contain all the serovars that the target population may encounter.  Even when the vaccine manufacturers figure out which serovars are circulating, a new serovar may emerge, rendering the vaccine ineffective as the new serovar spreads through the susceptible population.  The vaccine must then be reformulated at substantial cost.

This is exactly what happened to the leptospirosis vaccines that are given to dogs.³  The early canine vaccines, first available in the 1970s, contained the serovars Canicola and Icterohemorrhagiae.  These vaccines worked fine until the late 1980s or so, when new serovars started to appear in infected dogs, even in those that had been vaccinated.  Since then vaccine makers have added the serovars Grippotyphosa and Pomona to their vaccines.  Nevertheless with over 200 pathogenic serovars of Leptospira lurking out there, we don't know when or which additional serovars will emerge in the future.

It would be nice to have a single leptospirosis vaccine formulation that would protect against all serovars.  The protective effect of traditional vaccines is due to antibodies generated against lipopolysaccharide (LPS), whose structure differs among the serovars of Leptospira.  Since immunization elicits antibodies that recognize the LPS of only the serovars included in the vaccine, vaccinated individuals remain susceptible to infection by other serovars.

To get around this problem, scientists have been testing individual Leptospira surface proteins as potential vaccines in rodent models of leptospirosis.  Leptospira surface proteins tend to be antigenically conserved among the different serovars:  antibodies generated against a protein from one serovar often reacts against the same protein expressed by other serovars.  According to many studies the LipL32 and Lig surface lipoproteins, when delivered as recombinant proteins, naked DNA, or by microbial vectors (adenovirus and Mycobacterium bovis), apparently protected hamsters or guinea pigs from lethal infection by Leptospira.  Unfortunately one of the leaders in the leptospirosis field, Ben Adler (also an author of the two featured papers), has questioned the interpretation of these studies.⁴  He points out that the challenge strains used in several studies were not sufficiently lethal, making it easier to observe a protective effect of the vaccine.  Moreover some studies claimed statistically significant protective effects of the protein vaccine when in fact there was none upon Adler's reanalysis of the data.  The only protein to convincingly exert a protective effect in an appropriate animal model was LigA⁵ although the ability of the LigA subunit vaccine to cross-protect against different serovars of Leptospira has yet to be tested.  However there is one major problem with using LigA as a vaccine--not all Leptospira strains have the ligA gene.⁶

In the two studies described here the investigators took a step back from looking at individual proteins and developed an attenuated strain to use for immunization.  The properties of the attenuated strain, designated M1352, are described in the paper authored by Murray and colleagues.²  The M1352 strain was not developed by the classic approach of continuously growing and passaging the bacteria in culture until they lost their ability to cause disease.  Instead the strain was one of a large collection of mutants generated by random transposon mutagenesis of L. interrogans serovar Manilae.  The M1352 strain had the transposon inserted in a gene located in a large cluster of genes encoding enzymes that assemble LPS.  The mutation had subtle effects on the reactivity of M1352 with various antibodies raised against leptospiral LPS, suggesting that the LPS structure itself was somehow changed in M1352 when compared with the wild-type Manilae strain.

Since LPS is a crucial surface component that interacts with the host, it was not too surprising that M1352 was not able to cause lethal infections like its wild-type Manilae parent.  When they infected hamsters with the M1352 strain, the spirochetes were unable to kill the hamsters or even establish an infection in the kidneys.  Despite the efficient clearance of M1352, the Leptospira lingered long enough in the hamsters to provoke an antibody response. Western blots of L. interrogans lysates revealed strong reactivity of antibodies from the M1352-infected hamsters to a number of proteins. Because the M1352 strain generated an antibody response without establishing an infection, the authors decided to test the weakened strain as a vaccine in the hamster model in a follow-up study.¹

In the second study, Srikram and colleagues¹ demonstrated that immunization of hamsters with a single dose of live M1352 was more effective than a dose of heat-killed wild-type strain in protecting hamsters from being killed by the wild-type Manilae strain. The M1352 vaccine also did a better job in preventing colonization of the kidneys by the spirochete and in minimizing lung hemorrhage than the heat-killed vaccine.

When they challenged the vaccinated hamsters with a different serovar, a Pomona strain, all the hamsters immunized with live M1352 survived whereas 60% of animals immunized with heat-killed wild-type Manilae perished.  However the M1352 vaccine didn't work perfectly.  Although all hamsters immunized with live M1352 survived the challenge with the Pomona strain, the kidneys from 90% of the animals were culture positive, and 90% had hemorrhaged lungs.  Nevertheless this is the first time that complete protection from death was observed following challenge of vaccinated animals by a serovar unrelated to the vaccine strain.  They also showed that the M1352 vaccine had to be administered alive.  Heat-killed or chemically-killed M1352 vaccine failed to protect hamsters from lethal infection.

The investigators next tried to figure out which component of the M1352 strain was the protective cross-reactive antigen targeted by the hamster's immune system.  They wondered whether the live M1352 and heat-killed wild-type Manilae vaccines generated antibody responses to different proteins.  When they probed separate two-dimensional blots of L. interrogans membrane preparations of serovar Pomona with antibodies from hamsters immunized with M1352 and heat-killed wild-type Manilae, a number of protein spots lit up.  Most proteins, including LipL32, reacted with both sets of antibodies.  These proteins are unlikely to account for the cross-protection conferred by the M1352 vaccine since the presence of these antibodies in the hamsters immunized with heat-killed Manilae failed to protect the animals from being killed by the Pomona strain.  On the other hand, four Pomona proteins were recognized only by hamsters receiving the attenuated vaccine:

• Loa22, the only surface protein known to be essential for L. interrogans to cause lethal infections⁷
• a homolog of GspG, a component of the type II secretion system
• LA1939, a possible lipoprotein of unknown function
• OmpL36, a surface-exposed outer membrane protein of unknown function⁸

Since GspG is not a surface component of other bacteria and nothing is known about where LA1939 is located on Leptospira, Loa22 and OspL36 are the best candidates to test as potential cross-protective vaccines.

Featured papers

1. Srikram A, Zhang K, Bartpho T, Lo M, Hoke DE, Sermswan RW, Adler B, and Murray GL (March 15, 2011).  Cross-protective immunity against leptospriosis elicited by a live, attenuated lipopolysaccharide mutant.  Journal of Infectious Diseases 203(6):870-879.  DOI: 10.1093/infdis/jiq12


2. Murray GL, Amporn S, Henry R, Hartskeerl RA, Sermswan RW, and Adler B (November 2010).  Mutations affecting Leptospira interrogans lipopolysaccharide attenuate virulence.  Molecular Microbiology 78(3): 701-709.  DOI: 10.1111/j.1365-2958.2010.07360.x

Helpful references

3. Guerra MA (February 15, 2009).  Leptospirosis. Journal of the American Veterinary Medical Association 234(4):472-478.  DOI: 10.2460/javma.234.4.472

4. Adler B and de la Pena Moctezuma (January 27, 2010).  Leptospira and leptospirosis.  Veterinary Microbiology 140(3-4):287-296.  DOI: 10.1016/j.vetmic.2009.03.012

5. Silva, ÉF, Medeiros MA, McBride AJA, Matsunaga J, Esteves GS, Ramos JGR, Santos CS, Croda J, Homma A, Dellagostin OA, Haake DA, Reis MG, and Ko AI (August 14, 2007).  The terminal portion of leptospiral immunoglobulin-like protein LigA confers protective immunity against lethal infection in the hamster model of leptospirosis. Vaccine 25(33):6277-6286.  DOI: 10.1016/j.vaccine.2007.05.053

6. McBride AJA, Cerqueira GM, Suchard MA, Moreira MA, Zuerner RL, Reis MG, Haake DA, Ko AI, and Dellagostin OA (March 2009). Infection, Genetics and Evolution 9(2):196-205.  DOI: 10.1016/j.meegid.2008.10.012

7. Ristow P, Bourhy P, da Cruz McBride FW, Figueira CP, Huerre M, Ave P, Girons IS, Ko AI, and Picardeau M (July 2007).  The OmpA-like protein Loa22 is essential for leptospiral virulence. PLoS Pathogens3(7):e97. DOI: 10.1371/journal.ppat.0030097

8.Pinne M and Haake DA (June 2009).  A comprehensive approach to identification of surface-exposed, outer membrane-spanning proteins of Leptospira interrogans.  PLoS One 4(6):e6071. DOI: 10.1371/journal.pone.0006071

Tuesday, April 12, 2011

Dual role of TLR8 during the engulfment of Lyme disease spirochetes by human monocytes

For the first time scientists have shown that Toll-like receptor 8 (TLR8), a microbial RNA sensor located inside phagocytes, detects what is primarily an extracellular pathogen, the Lyme disease spirochete Borrelia burgdorferi.¹  As one may expect, the phagocytes secreted a mixture of inflammatory cytokines in response to the spirochete.  But they also expressed at least one of the type I interferons (IFNs), which until recent years were thought to be produced only in response to viral and intracellular bacterial infections.²

The phagocytes used for the study were human monocytes, which are the more easily available bloodstream form of the macrophages found in our tissues.  Macrophages are designed to capture and engulf microbial pathogens invading our bodies.  While sopping up the invaders, the macrophages send out warning signals in the form of cytokines and other inflammatory molecules to alert nearby cells and to get the immune system to send more immune cells to help defend the tissue under attack.

Most of the macrophage's microbial sensors belong to a family of related membrane proteins called Toll-like receptors (TLRs).  TLR1, TLR2, TLR4, and TLR6 span the plasma membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in membrane structures inside the cell.  Each TLR recognizes a specific component of microbes.  For example, TLR4 latches onto LPS; TLR2 forms a complex with TLR1 or TLR6 to bind the lipidated amino terminus of lipoproteins; TLR7 and TLR8 recognize single-stranded RNA; and TLR9 recognizes DNA.  Engagement of a TLR by a microbial component triggers a signaling cascade within the cell leading to the transcription of genes encoding inflammatory cytokines, which are then secreted.  Stimulation of TLR3, TLR4, TLR7, TLR8, and TLR9 can also activate transcription of genes encoding type I IFNs.  The exact response of the macrophage depends on which TLRs are engaged by the pathogen.³

In the PNAS paper by Cervantes and colleagues, the authors searched for the sensors triggered by B. burgdorferi.¹ It had been known for a decade that one of the sensors of B. burgdorferi is TLR2, which recognizes the many lipoproteins that populate the surface of the spirochete.  However, TLR2 can't be the only B. burgdorferi sensor in macrophages because a more recent study showed that mouse macrophages missing its Tlr2 gene continued to produce inflammatory cytokines, albeit at lower levels, while engulfing B. burgdorferi.⁴ This same study also showed that B. burgdorferi stimulated human monocytes to transcribe genes encoding type I IFNs and a number of genes known to be induced by type I IFNs.

The investigators first examined the effects of blocking phagocytosis of B. burgdorferi by treating the monocytes with cytochalasin D, a chemical that blocks phagocytosis.  They found that cytochalasin D prevented transcription of the gene encoding the type I interferon IFN-β and reduced the amount of the inflammatory cytokine TNFα secreted from the monocytes.  The little bit of TNFα that continued to be produced was probably a consequence of TLR2 being stimulated by B. burgdorferi lipoproteins on the surface of the monocytes.

Since the spirochetes had to be engulfed to observe the monocyte's complete response, an intracellular sensor must participate in sensing B. burgdorferi.  The investigators therefore focused their attention on the intracellular nucleic acid sensors TLR7, TLR8, and TLR9.  Earlier studies by many other labs have shown that engagement of these intracellular TLRs activated production of type I IFNs, so it made sense to examine these TLRs.

To figure out which TLR functioned as the intracellular sensor of B. burgdorferi, the investigators used synthetic fragments of DNA that specifically blocked each TLR without interfering with phagocytosis.  When they applied the inhibitors individually to the monocytes, they found that only the TLR8 inhibitor blocked induction of the IFN-β gene by B. burgdorferi (see right half of panel A below).  A synthetic DNA fragment that does not inhibit any TLR failed to block induction of IFN-β transcription.  Therefore, TLR8 was implicated as being the intracellular sensor that detects B. burgdorferi.  As a control, LPS, which is sensed by TLR4 but not TLR8, continued to induce synthesis of the IFN-β transcript in the presence of the TLR8 inhibitor (left half of panel A).

B. burgdorferi was added at a 10:1 ratio (bacteria:monocytes).  Following the 4-hour incubation period, IFN-β transcript levels were measured by quantitative real-time RT-PCR.  ODN, a control synthetic oligodeoxynucleotide; N.S., not significant; *, P < 0.05; **, P < 0.01 (Mann-Whitney U test)

When the investigators looked at the inflammatory cytokines being produced by the TLR8-inhibited monocytes, they discovered that TLR8 had another role in the monocyte's response to B. burgdorferi.  Blocking TLR8 reduced (but did not eliminate) the secretion of the inflammatory cytokines TNFα, IL-6, IL-1β, and IL-10 (see panel B below).  These results indicated that TLR2 and TLR8 both had to send signals the nucleus to maximize the amount of cytokines produced during engulfment of the spirochete.  The authors also found by indirect immunofluorescence microscopy that TLR2 and TLR8 were together in the phagosomal membrane surrounding the engulfed B. burgdorferi, which they saw were being destroyed.

The amount of cytokines secreted by the human monocytes was measured following the 4-hour incubation period.  "Un," no spirochetes added; "Bb," B. burgdorferi added at a 10:1 ratio (bacteria:monocytes)

So here's what the authors believe is happening during the encounter of human monocytes with B. burgdorferi.  The monocyte first contacts the spirochete at the surface of the plasma membrane.  The lipoproteins on the surface of the spirochete activate the TLR2 sensor on the surface of the monocyte, but the low local concentration of TLR2 in the plasma membrane hampers its full signaling potential.  As the monocyte engulfs the spirochete by phagocytosis, TLR8 and TLR2 are recruited to the phagosomal membrane surrounding the spirochete, which at this point is being destroyed by antimicrobial substances being dumped into the phagosome.  Destruction of the spirochete releases its RNA to stimulate TLR8, while the crowding of TLR2 in the phagosomal membrane enhances the signaling stimulated by lipoproteins.  TLR8 and TLR2 work together to send a signal to the nucleus to activate transcription of numerous genes, including those encoding inflammatory cytokines.  Signaling from TLR8 by a separate pathway also stimulates transcription of type I interferons.

So is TLR8 relevant to Lyme disease?  The authors make the reasonable assertion that TLR8 activation benefits those infected with B. burgdorferi in part by turning on the type I IFN response.

Given that type I IFNs can shape a variety of downstream inflammatory responses through positive and/or negative regulation of hundreds of additional genes involved in secondary host defenses, TLR8 activation is likely to play a critical role in clearance of the spirochete and more importantly, disease control. [emphasis mine]

Unfortunately, the research literature tells us that type I IFNs have a dark side.  Although the beneficial role of type I IFNs in fighting off viral infections is well established, whether they help or hurt us during bacterial infections is not always obvious.  Type I IFNs are clearly essential in combating some bacterial infections such as lethal bloodstream infections caused by group B streptococci, Streptococcus pneumoniae, and E. coli.²  As for Lyme disease, type I IFNs may help kill spirochetes, but they also promote joint inflammation in infected mice.⁵  To determine whether TLR8 contributes to Lyme arthritis, scientists will need to perform B. burgdorferi infection studies with Tlr8-knockout mice.


Featured paper

1. Cervantes, J.L., Dunham-Ems, S.M., La Vake, C.J., Petzke, M.M., Sahay, B., Sellati, T.J., Radolf, J.D., & Salazar, J.C. (2011). Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β Proceedings of the National Academy of Sciences, 108 (9), 3683-3688 DOI: 10.1073/pnas.1013776108


Key references

2. Mancuso G, Midiri A, Biondo C, Beninati C, Zummo S, Galbo R, Tomasello F, Gambuzza M, Macrì G, Ruggeri A, Leanderson T, & Teti G (2007). Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. Journal of Immunology, 178 (5), 3126-3133 PMID: 17312160

3. Kawai, T., & Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors Nature Immunology, 11 (5), 373-384 DOI: 10.1038/ni.1863

4.Salazar, J.C., Duhnam-Ems, S., La Vake, C., Cruz, A.R., Moore, M.W., Caimano, M.J., Velez-Climent, L., Shupe, J., Krueger, W., & Radolf, J.D. (2009). Activation of human monocytes by live Borrelia burgdorferi generates TLR2-dependent and -independent responses which include induction of IFN-β PLoS Pathogens, 5 (5) DOI: 10.1371/journal.ppat.1000444

5. Miller JC, Ma Y, Bian J, Sheehan KC, Zachary JF, Weis JH, Schreiber RD, & Weis JJ (2008). A critical role for type I IFN in arthritis development following Borrelia burgdorferi infection of mice. Journal of Immunology, 181 (12), 8492-8503 PMID: 19050267


Related posts

• Antigen presentation in the bloodstream:  How invariant NKT cells are activated by Lyme disease spirochetes

Thursday, February 24, 2011

Serologic testing for syphilis: missing the point

You may have seen several news sources touting the recent CDC finding that nearly one in five positive reactions with a newer syphilis test are wrong.  These headlines may grab the reader's attention, but the press took the finding out of context and failed to deliver the real message that the CDC was trying to convey.  Worse, the press reports may needlessly confuse and worry those who are being treated for syphilis.

Serological tests for syphilis are grouped into two categories.  Nontreponemal tests such as the VDRL and RPR are based on antibody generated against the lipid cardiolipin.  Presumably cardiolipin is released from damaged tissue in syphilis patients and gets incorporated into the membrane of Treponema pallidum.  The reason that these tests are "nontreponemal" is that antibodies to cardiolipin accompany many other conditions.  On the other hand, treponemal tests use T. pallidum proteins or even the entire spirochete as antigen to detect antibodies against the spirochete.  Although the classic treponemal tests such as the FTA-ABS (fluorescent treponemal antibody-absorption) and TP-PA (Treponema pallidum particle agglutination) are still used, the newer automated EIA (enzyme immunoassay) and CIA (immunochemiluminescence) treponemal tests enable clinical laboratories to rapidly screen a large number of sera.

The traditional approach to syphilis testing is to first screen the patient's serum with a nontreponemal test.  Since nontreponemal tests can give false positive reactions, reactive sera are retested with one of the treponemal tests.  However, the low cost of executing the automated treponemal tests have led some high-volume clinical laboratories to reverse the order of the assays:  they screen with the EIA/CIA treponemal test and confirm positive results with a nontreponemal test.  The CDC report in the Morbidity and Mortality Weekly Report deals with this so-called "reverse sequence" testing.

So where did the "nearly one in five" figure come from?  From 2006 to 2010, five large clinical laboratories screened 140,176 sera specimens with the reverse sequence procedure.  Of the 4,834 reactive with the EIA/CIA treponemal test, 2,743 gave negative results with the nontreponemal RPR test.  When the samples that gave discrepant results were tested further with one of the classic treponemal tests, 866 of the 2,743 samples were negative.  Overall, among the 4,834 samples that were reactive with the newer treponemal test, 866 or 18% were nonreactive with two subsequent tests.  These 866 were assumed to be false positives.

The news media pounced on the 18% figure and declared that hundreds may have been given antibiotics to treat a disease that they didn't have.  But they ignored the fact that doctors don't diagnose syphilis on the basis of a single lab test.  It is standard practice to perform a second test when the first comes back positive and to do even a third one if warranted.  Doctors also take into account the physical exam and the sexual and medical history of the patient before making the decision to treat with antibiotics.

Here's how the CDC responded to the assertion that those among the 18% may have been falsely diagnosed and treated unnecessarily with antibiotics:

There are two problems with this assertion. First, the current report does not document whether or not treatment was provided. Second, in those cases where treatment was provided, it may have been justified based on sexual risk and findings on clinical evaluation. It is also important to note that syphilis is not diagnosed on the basis of a single blood test. Many labs routinely will do additional testing when the first test is positive, without notifying the patient. Doctors diagnose syphilis after considering at least two syphilis tests, the patient's history, the physical exam, and a review of past syphilis test results. The MMMR analysis, while important, does not allow us to conclude that the newer tests led to inaccurate syphilis diagnosis or inappropriate treatment.

So what was the message that the CDC was trying to communicate to readers of the MMMR report?  Their intention was to provide guidance in the management of cases for which the reverse sequence screening is performed instead of the traditional sequence, which is still recommended by the CDC.  Specifically, when conflicting results occur (positive with the treponemal test, negative with the nontreponemal test), a third test should be done with the TP-PA.  (The CDC does not recommend the FTA-ABS because it is less specific and probably less sensitive.)  A positive reaction with the TP-PA indicates past or present syphilis; a negative reaction indicates that syphilis is unlikely.  As always, the clinical observations and medical history of the patient should also be considered in making an informed treatment decision.


Reference

Centers for Disease Control and Prevention (February 11, 2011).  Discordant results from reverse sequence syphilis screening -- five laboratories, United States, 2006-2010.  MMMR. Morbidity and Mortality Weekly Report 60(5):133-137.  link

Borrelia burgdorferi détectée par culture et PCR dans des cas de rechute clinique de borréliose de Lyme disséminée.

Borrelia burgdorferi détectée par culture et PCR dans des cas de rechute clinique de borréliose
de Lyme disséminée.
Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK. 1999.
Department of Medicine, Turku University Central Hospital, Finland. jarmo.oksi@utu.fi
Un total de 165 patients avec une borréliose de Lyme disséminée (diagnostiqués entre 1990-94, tous séropositifs
excepté un patient positif par culture) furent suivis après un traitement antibiotique, et 32 d’entre eux furent considérés
cliniquement comme ayant un échec thérapeutique. Sur 165 patients, 136 furent testés par PCR durant le suivi. La PCR
sur le plasma fut positive chez 14 patients entre 0 et 30 mois après l’arrêt du traitement, et 12 de ces patients avaient une
rechute clinique. De plus, la Borrélia burgdorferi fut cultivée dans le sang de trois des patients lors du suivi. Ces trois
patients appartenaient au groupe avec rechute, et deux d’entre eux étaient également positifs par PCR. Ce rapport se
focalise sur les 13 patients avec des rechutes cliniques et culture ou PCR positive. Huit des patients avaient des cultures
ou prouvées lors du diagnostic initial, le diagnostic des cinq restants était basé seulement sur une sérologie positive.
Tous les patients furent traités initialement pendant plus de 3 mois avec des antibiotiques intraveineux et/ou oraux (11
d’entre eux reçurent de la ceftriaxone, neuf pendant 2 semaines, un pendant 3 semaines et un pendant 7 semaines, suivi
par des antibiotiques oraux). Le traitement permit seulement un soulagement temporaire des symptômes du patient.
Tous sauf un avaient des résultats négatifs par PCR immédiatement après le premier traitement. Les patients furent
retraités habituellement avec de la ceftriaxone pendant 4-6 semaines. Aucun d’entre eux n’était positif par PCR après le
retraitement. La réponse du retraitement fut considérée comme bonne chez neuf des patients. Nous concluons que le
traitement de la borréliose de Lyme avec des antibiotiques appropriés pendant plus de 3 mois peut ne pas éradiquer le
spirochète. En utilisant la PCR il est possible d’éviter le retraitement des patients avec des « syndromes post Lyme » et
ceux avec des « cicatrices sérologiques » restant détectables des mois ou des années après l’infection.
- 1

Evaluation clinique et pathologique des infections chroniques à Bartonella henselae ou Bartonella clarridgiae chez les chats.

Evaluation clinique et pathologique des infections chroniques à Bartonella henselae ou
Bartonella clarridgiae chez les chats.
Kordick DL, Brown TT, Shin K, Breitschwerdt EB. 1999.
Department of Companion Animal and Special Species Medicine, Pathology, and Parasitology, College of
Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.
Les infections humaines à Bartonella donnent lieu à diverses présentations, alors que beaucoup de chats
apparaissent tolérer une bactériemie chronique sans anomalie clinique évidente. On innocula à dix-huit chats
sans pathogène spécifique des Bartonella henselae - et/ou Bartonnella claridgeiae- à partir du sang infecté de
chats et on les surveilla pendant 454 jours. Une bactériemie récidivante ne se corrélait pas avec des changements
dans les profils de protéines ou des différences dans la reconnaissance antigénique de protéine. Le test cutané
intradermique n'induisait pas de type de réaction d'hypersensibilité retardée au test antigénique cutané à la
maladie des griffes du chat. Treize chats furent euthanasiés à la fin de l'étude. En dépit d'infections persistantes,
les signes cliniques furent minimes et les résultats bruts de l'autopsie furent non remarquables. L'hytopathologie
révèla des hyperplasies des ganglions lymphatiques périphériques (chez les 13 chats), des hépatites
lymphocytaires (chez 6 chats), des myocartites lympho-plasmocytaires (chez 8 chats), et des néphrites
lymphocytaires interstitielles (chez 4 chats). Des structures suggestives de Bartonella furent visualisées dans
certaines sections teintées par Warthin-Starry, et l'ADN de Bartonella fut amplifié dans les ganglions
lymphatiques (chez 6 des 13 chats), le foie (chez 11chats) , le coeur (chez 8 chats), les reins (chez 9 chats), les
poumons (chez 2 chats), le cerveau (chez 9 chats). Cette étude indique que B. henselae et B. clarridgeiae peuvent
induire une infection chronique à la suite d'une transfusion de sang chez des chats sans pathogène spécifique, et
que l'ADN de Bartonella peut être détecté dans le sang, le cerveau, les ganglions lymphatiques, le myocarde, le
foie, les reins à la fois chez les chats ayant une culture positive à partir du sang et chez ceux ayant une culture
négative. La détection des changements histopathologiques chez ces chats supporte le rôle des espèces de
Bartonella dans une étiologie potentielle et le processus de plusieurs maladies idiopathiques.
- 2

Risques et prévention de la transmission de la babésiose et des autres maladies vectorielles à tiques par transfusion.

Risques et prévention de la transmission de la babésiose et des autres maladies
vectorielles à tiques par transfusion.
Cable RG, Leiby DA. 2003.
American Red Cross, Connecticut Blood Services, Farmington, and University of Connecticut Health Center,
Farmington, Connecticut 06032, USA. cabler@usa.redcross.org
OBJET DE LA REVUE : Les maladies vectorielles à tiques sont reconnues aux Etats-Unis comme problème de
santé publique. L’importance des maladies vectorielles à tiques a été accrue par la croissance des populations
animales ainsi que la croissance des loisirs dans les environnements boisés qui mènent à des piqûres de tiques.
La babésiose est causée par un hémoparasite, Babesia microti, transmise par les même tiques que la maladie de
Lyme, a des conséquences importantes sur la transfusion. Bien qu'il n'ai pas été reporté de transmission de la
maladie de Lyme par transfusion, des maladies nouvellements identifiées comme l'ehrlichiose pose des questions
supplémentaires dans le rôle des tiques dans les maladies transmises lors de transfusions.
DECOUVERTES RECENTES : le risque de transmission par transfusion de la babésiose est plus important que
généralement apprécié et dans les zones d'endémie représente un risque majeur pour la fourniture de sang. De
plus, la zone géographique de la B. microti s'étend, d'autres espèces de Babésia ont été impliqués dans la
transmission par transfusion dans l'ouest des Etats-Unis, et il résulte des déplacements des donneurs de sang et
des produits sanguins, l'apparition de babésiose transfusionnelle dans des zones moins familière de ces parasites.
En conséquence, un plus haut niveau de suspicion clinique permettra la découverte rapide et le traitement de ces
complications importantes de la transfusion sanguine.
RESUME : Dans les zones d'endémie la babésiose transmise par transfusion a une prévalence plus importante
que l'on ne le pense généralement. De l'extension de la zone géographique de différentes espèces de Babésias et
du mouvement des donneurs et des produits sanguins autour des Etats-Unis, il résulte que ne risque s'étend à des
zones non endémiques. Les cliniciens devraient maintenir un haut niveau de suspicion clinique pour les
babésioses transfusionnelles.

Transfert de l'infection à Borrélia burgdorferi s.s par transfusion dans le modèle murin.

Transfert de l'infection à Borrélia burgdorferi s.s par transfusion dans le modèle murin.
Gabitzsch ES, Piesman J, Dolan MC, Sykes CM, Zeidner NS. 2006.
Centers for Disease Control and Prevention, Division of Vector-Borne Infectious Diseases, Bacterial Zoonoses
Branch, Foothills Campus, Fort Collins, Colorado 80522, USA.
Sans traitement antibiotique, la bactérie causant la maladie de Lyme, la Borrélia burgdorferi peut être cultivée à
partir du sang périphérique humain de patients près de 6 semaines après la piqûre de tique. Pour déterminer si le
spirochète de la maladie de Lyme peut être transmis d'une souris donneuse spirochétémique à un receveur naïf
lors d'une transfusion de sang, le sang pris d'une souris immunocompétente infectée, fut transfusé soit à des
souris immunodéficientes (SCID), à des animaux consanguins immunocompétents (C3H/HeJ), ou à des souris
non consanguines. Neuf sur 19 (47,7%) des souris immunodéficientes, 7 des 15 (46,8%) des souris
immunocompétentes consanguines, et 6 des 10 (60%) des souris non consanguines devinrent infectées par la B.
burgdorferi après transfusion. Nos résultats indiquent qu'il est possible d'acquérir la B. burgdorferi par une
transfusion sanguine dans le modèle murin de la borréliose de Lyme.

Décroissance de la sous-population lymphocytaire CD57 chez les patients atteints de maladie de Lyme chronique.

Décroissance de la sous-population lymphocytaire CD57 chez les patients atteints de
maladie de Lyme chronique.
Stricker RB, Winger EE. 2001.
Département de Médecine, California Pacific Medical Center, 450 Sutter Street, Suite 1504, San Francisco, CA
94108, USA.
La maladie de Lyme chronique (ML) est une maladie débilitante causée par une infection vectorielle à tiques
avec le spirochète Borrélia burgdorferi. Bien que des anomalies immunologiques paraissent jouer un rôle dans
cette maladie , des marqueurs spécifiques de la ML n’ont pas été identifiés.
Méthode : Nous avons évalué 73 patients avec la ML chronique pour les anomalies dans les sous-populations
lymphocytaires en utilisant la cytométrie de flux. Sur ces patients, 53 avaient des symptômes musculosquelettaux,
tandis que 20 avaient des symptômes neurologiques prédominants. L’estimation de la durée de
l’infection allait de 3 mois à 15 ans, et tous les patients avaient des tests sérologiques positifs à B. burgdorferi.
Dix patients avec une ML aiguë (infection de moins d’un mois) et 22 patients avec le syndrome
d’immunodéficience acquis (SIDA) servirent de contrôle.
Résultat : Tous les 31 patients atteints de ML chronique ayant été testés avant traitement antibiotique ont des
niveaux significativement abaissés des lymphocytes CD57 (en moyenne 30 +/-16 cellules par micro-litre, la
normale étant entre 60 et 360 cellules par micro-litre, P<0.001). Dix-neuf des 37 patients (51%) qui furent testés
après avoir initié une antibiothérapie avaient des niveaux de CD57 (moyenne, 66 +/-39 cellules par micro-litre),
et tous les cinq patients testés après avoir achevé leur antibiothérapie avaient un nombre normal de CD57
(moyenne 173 +/-98 cellules par micro litre). A l’opposé tous les 10 patients ayant avec une ML aiguë et 82%
des patients avec le SIDA avaient des niveaux de CD57 normaux, et les différences entre ces groupes et le
groupe de malades de ML chronique n’ayant pas reçu de traitement est significative (P<0.001). Les patients
atteints de ML chronique avec des symptômes neurologiques prédominants ont des niveaux de CD57
significativement plus bas que ceux qui ont des symptômes musculo-squelettaux (30 +/-21 contre 58 +/-37
cellules par micro litre, P=0.002). Les niveaux de CD57 croissent chez les patients avec une ML chronique dont
les symptômes s’améliorent, alors que les patients avec une maladie réfractaire ont un niveau de CD 57 restant
bas.
Conclusion : Un niveau de sous-population lymphocytaire CD57 peut être un marqueur important d’une ML
chronique. Les changements dans la sous-population des CD57 peuvent être utiles pour surveiller la réponse à un
traitement dans cette maladie.

Invasion et effet cytopathogène tuant des lymphocytes humains par des spirochètes causant la maladie de Lyme.

Invasion et effet cytopathogène tuant des lymphocytes humains par des spirochètes
causant la maladie de Lyme.
Dorward DW, Fischer ER, Brooks DM. 1997.
National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, Montana
La maladie de Lyme est une spirochètose persistante de faible densité causée par la Borrélia burgdorferi sensu
lato. Bien que les spirochètes causant la maladie de Lyme sont hautement immunogènes dans les modèles
expérimentaux, le début des réponses spécifiques par anticorps à l'infection est souvent retardé ou indétectable
chez certains patients. Les propriétés et mécanismes intervenant dans une telle évasion immunitaire demeurent
obscurs. Afin d'examiner la nature et les conséquences des interactions entre les spirochètes de la maladie de
Lyme et les effecteurs immunitaires des cellules, nous avons co-incubé des B. burgdorferi avec des leucoytes
humains primaires et cultivés. Nous avons trouvé que la B. burgdorferi s'attache activement, envahi, et tue des
lymphocytes B et T humains. Une destruction significative commence dans l'heure suivant le mélange. Les effets
cytopathogènes varient en fonction du lignage des cellules hôtes, des espèces, de la vitalité et du degré
d'atténuation des spirochètes. La virulence spirochètienne et la susceptibilité lymphoytaire pourraient être toutes
deux sélectionnées phénotypiquement, et ainsi indiquer que les facteurs bactériens et ceux de la cellule hôte
contribuent toutes deux à de telles interactions. Ces résultats suggèrent que l'invasion et la lyse des lymphocytes
peut constituer des facteurs non reconnus de la maladie de Lyme et de la pathogenèse bactérienne.