BLyS drives affinity maturation

I have found an interesting paper that describes in the very detailed way how the interactions between two specialized subsets of lymphocytes which are germinal center (GC) B cells and follicular helper (FH) T cells may influence the affinity maturation of antibodies. The cooperation of these two subsets is known for the long time. However, the novelty this publication brings about is that it looks specifically at the germinal center reaction and dissects the role that the molecule called BLyS (or interchangeably BAFF) may play in the affinity maturation of antibodies from other tasks fulfilled by the same protein. In other words, BLyS has important functions in many aspects of B cells life and the exact definition of its role in the affinity maturation process was not possible using relatively straightforward methods like studying mice with deletion of gene encoding BLyS.

The link:

Authors perform the study on mice that were immunized with nitrophenacethyl hapten conjugated with chicken gamma globulin which is a widely used method to elicit a strong germinal center reaction. What forms the basis of this paper is the observation that receptor-bound BLyS seems to be selectively excluded form B cells that are located inside germinal centers. Investigators follow with the demonstration that activated B cells downregulate TACI (one of three BLyS receptors), that IL-21 may be responsible for the observed TACI downregulation and finally that in the context of germinal center (and unlike systemically) the main source of BLyS comes from cells of hematopoietic origin, namely follicular helper T cells.

But what role the T cell-derived BLyS may have for the quality of the antibody response? To answer this question authors create an experimental setting (mixed bone marrow chimeras) where the T cell lineage lacks BLyS. In such circumstances germinal centers do form and are maintained mostly normally. However, the ability to form high-affinity antibodies is visibly impaired when germinal centers operate without T-cell derived BLyS.

Radhika Goenka, Andrew H. Matthews, Bochao Zhang, Patrick J. O’Neill, Jean L. Scholz, Thi-Sau Migone, Warren J. Leonard, William Stohl, Uri Hershberg, and Michael P. Cancro (2014). Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation Journal of Experimental Medicine DOI: 10.1084/jem.20130505

Observations on the B cell repertoire in young and elderly people

Since I have not written for a while I decided to choose for my comeback something that could be summarized in couple of shorts paragraph, something that I am not very familiar with, so I am not grounded in endless divagations yet something that is of enough interest to whet my appetite for more posts to come soon. I selected an article that compares the overall B cell repertoires between humans that are respectively young or elderly as well as brings an additional variable to the age parameter, that is the seropositivity for either CMV or EBV.

The link:

This is a study in which authors analyze the rearanged heavy chain gene sequences from PMBC cells isolated from peripheral blood of study participants that are assigned to three different age group. Additionally all collected samples were assessed for the presence of anti-CMV or EBV antibodies. The conclusions could be put in a nutshell in few sentences. There seems to be no difference in V, D and J usage between young and elderly age groups. However, the older age appears to correlate with lengthening of the CDR3 region. People advanced in years also harbor more highly mutated IgM and IgG Ig genes and some of them display a trend towards the accumulation of expanded and persistent B cell clones. Last but not least, either the chronic infection with CMV or EBV appears to imprint its own discreet mark on the overall B cell repertoire.

Krishna M. Roskin, Tho D. Pham, Jonathan Laserson, Chen Wang, Yi Liu, Lan T. Xu, Katherine J. L. Jackson, Eleanor L. Marshall, Katie Seo, Ji-Yeun Lee, David Furman, Daphne Koller, Cornelia L. Dekker, Mark M. Davis, Andrew Z. Fire and Scott D. Boyd (2014). Effects of Aging, Cytomegalovirus Infection, and EBV Infection on Human B Cell Repertoires. Journal of Immunology DOI: 10.4049/jimmunol.1301384

IL-13 and hepatic gluconeogenesis

When I started learning about immunology I held a conviction that the immunity serves only to combat infections and pathogens. Perhaps the major change I have acquired in my understanding of immune processes is that the function of the immune system could be more permeating and extend to broader activities than just the defense. What we call the immune system works in situations well beyond the strict response to pathogenic organisms. It does not necessarily fight foreign entities as it may accommodate them (in case of microbiota) and also it has the intriguing links with the metabolism. I have found a publication that adds an interesting voice in support of such more general role of the immune system. It turns out that the cytokine IL-13 which is an important player in Th2 branch of immunity may influence how our body maintains one of the most important metabolic indicators.

The link:

Authors show data that mice deleted for gene encoding IL-13 display the impaired control of glucose level in the blood. Such defect appears to be a systemic one since it comprises both the increased production of glucose by liver cells as well as the reduced glucose uptake by muscles. Additionally, investigators delve into the molecular mechanism that underlies the IL-13-dependent control over the glucose production in the liver. It turns out that the transcription factor STAT3 could be the mediator between IL-13 signaling and genes involved in hepatic gluconeogenesis. Other than that authors attempt to identify the cellular population which may be responsible for the release of IL-13 in the liver and suggest that these could be NKT cells.

I am not really sure if it is sound to speculate in such way but there is at least the theoretical possibility that the exposure to parasites that provoke Th2-skewed response (like helminths) could protect from developing type II diabetes. The only problem is that relatively benign organisms inhabit the gastrointestinal tract and their influence may not extend to the liver whereas those that infect systemically (like Schistosoma mansoni) are too dangerous to be treated as a therapeutic agent. However, schistosome eggs are already applied as support in the treatment of excessive gut inflammation. May they be helpful in the regulation of glucose level?

Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR, Inouye K, Barlow JL, Ji Y, Mizgerd JP, Qi L, Shi H, McKenzie AN, & Lee CH (2013). Direct control of hepatic glucose production by interleukin-13 in mice. The Journal of clinical investigation, 123 (1), 261-71 PMID: 23257358

Schistosoma mansoni evacuates its eggs through Peyer’s patches

Schistosomes are parasitic worms that live in the blood and have a complicated life cycle. The sexual form inhabits vertebrates (humans included) whereas the other stages infest fresh water snails. Adult worms tend to chronically infect their host (sometimes for many years) but for the propagation they have to be able to release their eggs to the outer environment. These blood parasites are remarkably invisible to the immune system; however, their eggs are known to induce the immune response. How such ability may connect to the propagation issue is the subject of the recent publication.

The link:

Authors study how Schistosoma mansoni, which is an endemic human parasite present in many tropical regions of the world, may excrete its eggs through the intestinal barrier (schistosome species vary between utilization of the intestinal and urinary tracts as the evacuation routes for eggs). It looks like to this end the parasite uses the lymphatic structures encountered in the lower portion of the small intestine – Peyer’s patches. The presence of mature schistosome eggs is apparently able to remodel the vasculature around Peyer’s patches and introduce changes to the cellularity of these intestinal lymphatic structures. Moreover and crucially, in the strain of mice that harbors no Peyer’s patches the egg excretion is visibly reduced and more eggs appear to be backwashed into the host tissue where they form granulomas.

For a number of years schistosome eggs have been hyped as the “taming agent” of the over-reacting immune system. It is well known that they possess the modulatory influences over a number of inflammatory conditions that afflict the gastrointestinal tract. I wonder if such an ability to modulate may be due to the described peculiar interaction of schistosome eggs with their hosts’ Peyer’s patches. From the schistosome point of view eggs need to get out. Thus the parasite may have evolved to drive the immune reaction to its eggs because of the necessity to utilize immune structures for the egg excretion.

Joseph D. Turner,Priyanka Narang,Mark C. Coles,Adrian P. Mountford (2012). Blood Flukes Exploit Peyer’s Patch Lymphoid Tissue to Facilitate Transmission from the Mammalian Host PLOS Pathogens

Memory CD4 T cells and the neonatal gut

I have found a short paper on the potential mechanism of how HIV virus may be transmitted between mother and child. I think it is interesting because it not only provides the information which may be useful for a given pathology but it also poses some questions as to the basic immunology processes. The main theme of the paper is the quest for HIV targets among neonatal CD4 T cells. As it is known the virus tends to infect memory CD4 T cells but these cells are practically absent in the cord blood. Thus authors inspect neonatal CD4 T populations from various anatomical compartments and find that CD4 T cells bearing a memory marker and HIV co-receptor abound at the intestinal mucosa.

The link:

CD4 T cells collected for this study derive from children born to healthy mothers therefore this report asks only about the potential mechanism of mother to child transmission. Authors follow CD4 T cells that bear also CD45RO (which is a marker of memory state) and CD5 (HIV uses this molecule as a co-receptor to infect an individual cell – only CD5-tropic strains tend to become transmitted form mother to child). The main conclusion of this publication is that the population of CD4+CD45RO+CD5+cells (the potential HIV target according to the current state of knowledge) exists at the neonatal gut mucosa but not in the lymph nodes, spleen or blood. Additionally, around half of this intestinal memory CD4+CD45RO+CD5population appears to be differentiated into Th17 phenotype since these cells express RORγt transcription factor and CCR6.  In an in vitro experiment investigators also show that neonatal CD4 T cells from the gut are more susceptible to HIV infection than CD4 T cells from the lymph nodes or blood.

Based on obtained data authors propose a model of how HIV gets transmitted from mother to child. According to them the virus may take the oral route of transmition by the ingestion of infected body fluids during the delivery or milk shortly afterwards. I lack the clinical knowledge to critically evaluate such proposal. But I have more basic question instead. This paper not only shows the presence of memory CD4 T cells population at the neonatal gut mucosa but it also provides the evidence that these memory cells underwent substantial clonal expansion that must have happened in utero. I would like to know more details on the nature of antigenic challenge that underlies such prenatal activation of the adaptive immune system.

Bunders MJ, van der Loos CM, Klarenbeek PL, van Hamme JL, Boer K, Wilde JC, de Vries N, van Lier RA, Kootstra N, Pals ST, & Kuijpers TW (2012). Memory CD4+CCR5+ T cells are abundantly present in the gut of newborn infants to facilitate mother-to-child transmission of HIV-1. Blood, 120 (22), 4383-90 PMID: 23033270

On the wild mice and autoimmunity

Only the relatively small part of mammalian genome is formed by protein-coding sequences. The long stretches between these protein-bearing fragments contain other components which could be either non-transcribed regulatory elements or the variety of non-translated RNAs many of which are also taking part in the regulation of gene expression. This intricate network influences the decision whether a given protein is present in the particular physiological situation and how much of it is available. Therefore the issue how proteins are regulated may in fact be equally or more important than the structural differences in coding parts of the protein in question. The problem of transcriptional regulation that affects the autoimmunity development composes the leading theme of the publication I am discussing today. Like the majority of experimental studies this work uses the cornerstone model organism – the mouse Mus musculus. However, unlike the most it provides also some glimpse into the natural populations of rodents.

The link:

The particular problem analyzed by this publication comprises the association between FcγRIIb receptor and the aptitude to develop autoimmune reactions. Authors analyze the populations of wild mice from various part of the globe and find out that the vast majority of them are in the possession of FcγRIIb haplotype that is also present in several laboratory mice known for their propensity to develop the autoimmunity. Such arrangement is of interest because it suggests that in the wild populations such autoimmunity-correlated variant of FcγRIIb may actually be positively selected.

FcγRIIb is the receptor that recognizes the constant portion of an antibody that has switched to the IgG isotype and unlike other receptors that also bind to IgG its ligation on B cells causes the modulation of immune responses. To gain an insight of how FcγRIIb haplotype which is predominantly present in the wild mice may influence the immune response of the classic laboratory strain C57BL/6 (which itself has FcγRIIb haplotype not associated with the autoimmunity) investigators exchange the copies of that receptor by the knock-in approach and study the immune parameters of the resulting strain.

It turns out that the alterations between two haplotypes lie in their transcriptional regulation. In the non-autoimmune setting (as demonstrated by C57B/6 strain) FcγRIIb is upregulated on germinal center B cells whereas the knocked-in variant of this receptor cancels this up-regulation. Additionally, when compared to to C57BL/6 line the novel knock-in strain displays the reduced amount of FcγRIIb on activated B cells, splenic transitional B cells and bone marrow residing pre-B cells. Authors pin down the difference in the DNA sequence that underlies the disparate regulation of two variants and propose the transcription factor which may be responsible for the up-regulation seen when the non-autoimmune haplotype is present. Finally, investigators also show that the two haplotypes in questions differ in qualitative terms that comprise the number of germinal center B cells, affinity maturation and autoimmunity development.

Why do I think that this report is interesting? When you look at the paper conclusions from the broader perspective they seem to confirm the notion that in the natural circumstances the autoimmunity is not a problem. The widespread presence of that particular FcγRIIb haplotype among the wild mice suggests that at least for germinal center B cells the natural selection may have favored the situation where the efficiency of immune reaction is maximized even at the cost of potential collateral damage. Maybe it looks like the obvious notion but it is good to have some hard data that confirm it.

Espeli, M., Clatworthy, M., Bokers, S., Lawlor, K., Cutler, A., Kontgen, F., Lyons, P., & Smith, K. (2012). Analysis of a wild mouse promoter variant reveals a novel role for Fc RIIb in the control of the germinal center and autoimmunity Journal of Experimental Medicine, 209 (12), 2307-2319 DOI: 10.1084/jem.20121752

First prime and then pull – the novel immunization approach

Some areas of our body enjoy a special status as far as the immune reaction is concerned. Anatomical entities like the gut or female genital tract as well as other mucosal surfaces do not support the same extend of protective response compared to many non-mucosal tissues. This exclusion is crucial to avoid the unwanted inflammation in places that are regularly exposed to the outer environment but sometimes it may present a problem when there is the need to elicit the strong protective response at such privileged site. I have found an interesting report which applies the novel vaccination strategy aimed to enhance the protection against herpes simplex virus 2 which being the virus transmitted through the contact with infected body fluids often enters the body through the genital organs. The innovation that this report introduces consists of double treatment (“prime and pull”) which bypasses the restrictive entry of memory T cells into the vaginal mucosa.

The link:

The mentioned “prime and pull” strategy is the subcutaneous immunization with an attenuated strain of HSV-2 (prime) which is followed by the topical application of chemokines CXCL9 and CXCL10 to the vaginal mucosa (pull). Authors follow the localization of CD8 T cells that recognize an epitope within one of HSV-2 glycoproteins and activated CD4 T cells to show that the distal immunization event plus the localized chemokine treatment provokes the significant recruitment of activated lymphocytes to the vagina whereas the immunization alone has much weaker effect. Interestingly, this recruitment is specific to CD4 and CD8 lymphocytes and does not encompass other cell types that express the relevant chemokine receptor CXCR3.

Is the “prime and pull” approach able to provide the longstanding and reliable protection? Data demonstrate that CD8 T cells (but not CD4 T cells) are retained at vaginal mucosa after the primary response period is over. Most importantly the “prime and pull” treatment may be indeed superior in enforcing the better protective immunity to HSV-2 challenge than the immunization alone. Investigators also ask about the mechanism by which the protection is delivered by the “prime and pull” strategy. It appears that this application can prevent the virus from entering the nervous system where HSV-2 propagates past the mucosal stage of infection.

What will be the future of “prime and pull”, though? The pros are obvious – there is the simple method to enhance the mucosal migration of protective lymphocytes without the “ugly face” of immunity which in this case would be the excessive inflammation at the sensitive anatomical location. Authors speculate about the future applications ranging from HIV protection to solid tumors treatment. The method itself may also be developed as in the discussed paper it provides the optimal protection only in conjunction with the adoptive transfer of virus-specific lymphocytes. The “pull” works as well with the endogenous population of CD8 T cells; however, the protection is suboptimal in such scenario. I will follow this story.

Shin H, & Iwasaki A (2012). A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature, 491 (7424), 463-467 PMID: 23075848

The own versus foreign microbiota

It was long known that the absence of the gut microbiota impairs the full functionality of mammalian immune system. However, it appears that the immune system may require the species-specific microbiota not just any microbiota to develop its proper responses as the recent publication indicates. I think that this report has important implications both for the better understanding of principal immune events as well as for predicted and much expected innovative research applications like the advent of experimental animals with humanized microbiota.

The link:

In the course of this research authors colonize germ-free mice (it means – without any microbiota) with intestinal bacteria that are derived from several sources. Two main of these sources are murine or human fecal samples. Additionally, some experimental mice are also provided with rat microbiota. Summarizing the applied methodology, the starting fecal material (murine, human or rat) serves to prepare a respective probe that provides the formerly germ-free mice with commensal bacteria which differ by the species origin.  Using such model the publication answers two outstanding questions. The first analyzes how different species microbiotas are accommodated inside the murine intestinal tract by looking what is the difference between the original colonization sample and the established microbiota. The second attempts to find out what could be the influence of incongruent microbiota (in this case human or rat-derived) for the development of murine immune responses that are known to be affected by commensal bacteria.

Obviously, humans and mice harbor different microbiotas and data obtained by investigators reflect this simple fact as species identification among two different experimental microbiotas (murine or human-derived) reveals quite dissimilar results. But what is really interesting involves how, or maybe rather to what extend human-derived commensal bacteria could be maintained inside the murine gastrointestinal tract. It appears that recipients of human microbiota demonstrate a period of instability to their intestinal bacterial community after which a constant state is achieved. However, the final microbiota of such mice differs remarkably from the original sample. This is not the case for animals that received murine microbiota. Thus human intestinal commensals cannot be maintained in mice in their entirety. Additional and important piece of information is that Firmicutes may contain the bulk of bacterial species that are specific to humans and unstable in mice.

What is even more striking – mice colonized with human microbiota resemble germ-free mice in many immune parameters that are normally influenced by the presence of commensal bacteria. Studying such mice investigators document many changes in the immune structures of the small intestine such as smaller number of T cells in the lamina propria, less αβ CD4 T cells in the intraepithelial compartment, smaller Peyer’s patches and less T cells inside Peyer’s patches. The large intestine of mice with human microbiota is also affected but in quite contrasting way since it holds less γδ T cells in the intraepithelium but there are no other changes. Peripheral immune organs like spleen or brachial lymph nodes seem to be not altered by the change in microbiota origin. As an additional argument for the need of species-specific microbiota in the proper development of mucosal immune responses authors provide germ-free mice with rat-derived microbiota and observe similar disfuntionalities of the intestinal immune system as in the case of human microbiome transfer.

When it comes to the mechanism responsible for the impaired accumulation of lymphocytes at intestinal sites in mice with humanized microbiota it looks like it is the proliferation in Peyer’s patches and mesenteric lymph nodes that may be hold accountable. On the other hand the gut homing ability seems to not be affected by the heterologous microbiota transfer. Among other results that this publication contains the observation that the colonization with different species microbiota causes different bias in T cell effector phenotypes compared to the colonization with homologous microbiota definitely merits the further attention. Authors come to such conclusion after performing the detailed transcriptional analysis of CD4 T cells from lamina propria isolated from mice that were given the transfer of either murine or human commensal bacteria.

The commentary that I would like to make concerns the differential ability of murine or human microbiotas to stimulate the proliferation of CD4 T cells at mucosal sites. CD4 T cells proliferate as the response to the antigen stimulation and since they bear anticipatory receptors (the true cornerstone of adaptive immunity) the obvious question that comes to mind is why the origin of microbiota matters that much. I do not have explanation for this unexpected result and authors also do not offer a definitive answer, although they make some intelligent guesses as to the potential reason why heterologous microbiota fail to stimulate CD4 T cells proliferation to the same extend as murine commensals (impaired antigen uptake, decreased ability to penetrate mucus layer). An interesting observation is that the host epithelium seems to be more proficient at detecting host-specific than foreign bacteria. Perhaps the stratification by mucus layer is not as stringent in the case of certain host-specific bacterial species.

My last remark touches more practical thing. I have read recently a number of eloquently written review articles that postulated the need to engineer experimental mice with humanized microbiota as the exciting models to study microbiota-influenced diseases like inflammatory bowel disease or metabolic syndrome. But in the light of data that this publication presents the generation of such models looks more complicated than it was thought before. Obviously it is pertinent now that these findings be revisited by other laboratories. The following studies may confirm, widen or even contradict the conclusion presented in the discussed paper. However, maybe we assumed just too much and did not take into account the deep symbiotic relationship between host and its specific commensal bacteria that may be very difficult to recapitulate in a heterologous model.

Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, Reading NC, Villablanca EJ, Wang S, Mora JR, Umesaki Y, Mathis D, Benoist C, Relman DA, & Kasper DL (2012). Gut immune maturation depends on colonization with a host-specific microbiota. Cell, 149 (7), 1578-93 PMID: 22726443

Non-pathogenic SIV infection and type-I interferon signaling

How monkeys or apes respond to the challenge of lentiviral immunodeficiency viruses varies across different primate species. Some primates like rhesuses are similar to humans because following SIV infection they develop the AIDS-like disease with all the characteristic features of progressive immune destruction. However, there are other species that do not display such aggravated pathology. African sooty mangabeys are the best studied example among these AIDS-refractory animals. Infected sooty mangabeys do not clear the virus but seem to have adapted to live with it. Such infection lasts for life but it is the relatively mild condition without the continuous depletion of memory CD4 T cells and the chronic immune activation that are associated with human or simian AIDS. The current clinical efforts in humans aim at the reduction of damage caused by the infection and slowing down the progression to AIDS. Thus the detailed knowledge of how AIDS-refractory species achieve their status might be instructive and there is the respective research avenue devoted to studying these species. I have found the publication that looks at the role of type-I interferon signaling during the chronic phase of SIV infection in a species that does not progress to AIDS.

The link:

Authors attempt to clarify the interactions between the presence of the augmented type-I interferon signaling and the immune response in the chronic phase of SIV infection. Their rationale is simple – since the up-regulation of interferon signature genes correlates with HIV/SIV infections that progress to AIDS, so what may happen if artificially boost the expression of these genes during the non-pathogenic SIV infection? To this end they choose several naturally infected sooty mangabeys and subject them to the treatment with type-I IFN agonist which procures strong but transient enhancement in the expression of interferon signature genes.

To obtain the answer to their question investigators focus on how the increased type-I interferon signaling influences several relevant immune parameters. Acquired data are compared to the baseline values that were observed before the onset of treatment (no control group is included in this research due to availability reasons). The studied parameters comprise the range of CD4 T cells depletion (an indicator of the immune system impairment), the activation and proliferation levels of CD4 T cells (indicators of the chronic immune activation) as well as the intensity of anti-SIV CD8 response.

The take-home message from this report is that the administration of type-I interferon agonist does not impact any of immune parameters that were tested but it only brings down temporarily the viremia level (after all, type-I IFN is regarded as the anti-virus defensive molecule). What does it mean for the understanding of non-pathogenic SIV infection? The mechanisms responsible for the AIDS-refractory status are most probably complex, robust and might not depend on just one particular pathway.

Vanderford TH, Slichter C, Rogers KA, Lawson BO, Obaede R, Else J, Villinger F, Bosinger SE, & Silvestri G (2012). Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood, 119 (24), 5750-7 PMID: 22550346

Enter the mycobiota

I have found the publication that focus on pretty much unexplored subject which is the presence and role of commensal fungi in the mammalian gastrointestinal tract. As far as I know there is no information on whether the intestinal fungi community (similarly the bacterial microbiome) has any influence on the basic metabolic functions of their hosts. The discussed paper does not provide such knowledge either. Instead it attempts to establish a link between the increased susceptibility to colitis and the inability to respond properly to fungal wall components (through the lack of the innate receptor Dectin-1) as well as it makes the initial analysis of murine mycobiome. Although it is probably too early to draw such conclusion, my impressions are that there might be differences in the very basics rules of cohabitation between mammals and intestinal fungi compared to mammals/commensal bacteria interactions.

The link:

Authors confirm the presence of fungi in the gastrointestinal tract with two methods – the first detects the specific fungal RNA whereas the second visualizes fungal cells with soluble Dectin-1 probe (Dectin-1 recognizes β-1,3-glucans from fungal cell wall). The biggest fungal concentration is found in the colon which is also the place where commensal bacteria reach their highest density. However, the bulk of data is devoted to the analysis how the absence of Dectin-1 (which as mentioned above is the fungi-specific innate receptor linked to the inflammasome pathway) may influence the colitis development. The most important finding in that aspect is that the lack of Dectin-1 procures significantly worse colitis outcome in the mouse model that applies DSS-induced injury. Also the polymorphism in human gene encoding Dectin-1 is linked to the severe form of disease recognized as MRUC (medically refractory ulcerative colitis).

The publication contains other interesting data that allow very initial comparison between the characteristics of microbiome and mycobiome. One of important terms that describe a specific interaction between intestinal bacteria and their host is “dysbiosis”. The dysbiosis occurs when the gastrointestinal tract holds the abnormal microflora composition which appears to be able to influence the predisposition to maladies like gut inflammation or metabolic syndrome malfunctions. An interesting example of dysbiosis develops when animals are deficient for the innate receptor that recognizes bacterial flagellin (TLR5) which is a dominant immune activator in the gut. Remarkably, in some cases this pathogenic microflora setup has been shown to be transferable between different specimens as the sheer cohabitation of experimental animals (which is meant to expose them to each other microbiota) may change their susceptibility to certain diseases (consult the following report for an example: Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature; 2012. 482: 179-85). Authors test whether the absence of Dectin-1 could trigger any disease-facilitating microflora variations by crisscross transferring of microflora (not discriminating between bacteria and fungi) from either wild type animals or animals with Dectin-1 deficiency. However, such exchange does not influence the severity of DSS-provoked colitis which in this case looks to be determined by the host genetic background only.

The key in the understanding of the unique interactions between microbiota and immune system is the mutual interdependence of bacteria and their hosts. Nobody knows if this is the case for intestinal fungi; however, the initial data (with the emphasis on “initial”) coming from this report suggest something else. Investigators perform the assessment of murine intestinal mycobiome by sequencing and find that although there is enough diversity in the species arrangement, most data derive from a single organism – Candida tropicalis. This fungus is an opportunistic pathogen and authors confirm that it can play a role in the colitis development. Could intestinal fungi be just free riders?

Iliev ID, Funari VA, Taylor KD, Nguyen Q, Reyes CN, Strom SP, Brown J, Becker CA, Fleshner PR, Dubinsky M, Rotter JI, Wang HL, McGovern DP, Brown GD, & Underhill DM (2012). Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science (New York, N.Y.), 336 (6086), 1314-7 PMID: 22674328