• Eric Muraille's Research Group
  • Eric Muraille's Research Group
  • Eric Muraille's Research Group

Research

 

Pathogens selected, along evolution, molecular mechanisms allowing them to colonize, feed and proliferate on or inside host organisms. In turn, host developed an immune system to control infection by pathogens. Despite many advances, infectious diseases remain the major causes of morbidity and mortality in much of the world. A growing number of clinically relevant infectious diseases have been reported to be characterized by pathogen persistence in the host that implicate long-lasting and costly therapy. Strategies to control these infections fail in part due to our poor understanding of the factors that orchestrate host protective immune responses in vivo.

 

Experimental study of Brucella infection in mice

Brucellosis, also known as “undulant fever”, “Mediterranean fever” or “Malta fever”  is one of the most common bacterial zoonosis world-wide, with more than half a million estimated new cases each year. Brucellosis affects a large range of mammals and is caused by facultative intracellular Gram-negative alphaproteobacteria of the genus Brucella. Brucella display strong tissue tropism for the reticuloendothelial and reproductive systems with a stealthy intracellular lifestyle that limits exposure to protective immune responses. Brucella has evolved multiple strategies to evade immune response mechanisms to establish persistent infection and replication within host.

 

Human brucellosis is transmitted through ingestion, inhalation, or contact of contaminated animal products with the conjunctiva or skin lesions. The majority of cases are caused by ingesting unpasteurized milk or cheese from infected goats or sheep. Person-to-person transmission is rare. The disease causes flu-like symptoms, including fever, weakness, malaise and weight loss. The disease can be very insidious and may present in many atypical forms. In many patients the symptoms are mild and, therefore, the diagnosis may not be even considered. Indeed it should be noted that even in severe infections differential diagnosis can still be difficult. Brucella can cause a devastating multi-organ disease in humans with serious health complications in the absence of prolonged antibiotic treatment. Despite significant progress, the incidence of human brucellosis remains very high in endemic areas and is considered to be largely underestimated. In addition, Brucella species have been “weaponized” by several governments and are presently classified as category B threat agents. As complete eradication of Brucella would be unpractical due to its presence in a large range of wild mammals and because antibiotic treatment is costly and patients frequently suffer from resurgence of the bacteria, vaccination remains the most rational strategy to confer durable protection on populations living in endemic countries and professionals frequently exposed to Brucella. Unfortunately, there is currently no available human brucellosis vaccine as all commercially available animal vaccines are live vaccines which would cause disease in humans.

 

Our group is working on several different aspects at the interface between the host and Brucella spp in experimental mouse models.

 

  • The identification of immune effector mechanisms implicated in the control of Brucella growth in vivo

Brucella spp. are characterized as stealthy pathogen that can persist lifelong in their hosts. Our objectives are (i) the identification of immune effector mechanisms implicated in the control of Brucella growth in vivo (ii) the characterization of reservoir cells allowing the persistence of Brucella in vivo. Infection is induced by intranasal inoculation in the mouse experimental model.

 

  • The characterization of reservoir cells allowing the persistence of Brucella in vivo

We used mCherry-expressing Brucella melitensis strain to analyze in situ the phenotype of infected cells. We recently identified erythrocytes as a reservoir cells for Brucella in vivo and characterized the phenotype of splenic Brucella reservoir cells in spleen from susceptible mice.

 

  • The identification of bacterial genes required to infect and perform cell cycle in  alveolar macrophages in vivo.

We used Tn-Seq strategy to identify the bacterial genes indispensable to each step of Brucella infection par intranasal way in mice.

 

  • The impact of host immune status on the control of Brucella melitensis

In order to analyze the impact of unrelated infection or inflammatory disease on the control of Brucella melitensis infection, we have developed several model of cross-pathology. We studied the impact of Trypanosoma infection and allergic asthma (Derp1, Alternaria) on Brucella infection (cross-pathology models).

 

 

Theoretical studies

"Science is made with facts, as a house is made with stones: but an accumulation of facts is no more a science than a heap of stones is a house".

Henri Poincaré

 

Theoretical thinking is often neglected by scientists for its excessive abstraction and its lack of use in the everyday life. However, theoretical framework or paradigms are indispensable in experimental science. They define the experimental ways to explore a natural phenomenon and give meaning to observations and data. Unfortunately, a negative aspect of paradigms is that they act as "perception filter". They focus attention on some fact but lead to ignore others. Based on interdisciplinary approach (immunology, microbiology, evolution theory, system theory), I tried to revisiting some dominant paradigms in Immunology.

 

  • The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences.

Acquired immunity against infectious disease (AIID) has long been considered as strictly dependent on the B and T lymphocytes of the adaptive immune system. Consequently, AIID has been viewed as highly specific to the antigens expressed by pathogens. However, a growing body of data motivates revision of this central paradigm of immunology. Unrelated past infection, vaccination, and chronic infection have been found to induce cross-protection against numerous pathogens. These observations can be partially explained by the poly-specificity of antigenic T and B receptors, the Mackaness effect and trained immunity. In addition, numerous studies highlight the importance of microbiota composition on resistance to infectious disease via direct competition or modulation of the immune response. All of these data support the idea that a non-negligible part of AIID in nature can be nonspecific to the pathogens encountered and even of the antigens expressed by pathogens. As this protection may be dependent on the private T and B repertoires produced by the random rearrangement of genes, past immune history, chronic infection, and microbiota composition, it is largely unpredictable at the individual level. However, we can reasonably expect that a better understanding of the underlying mechanisms will allow us to statistically predict cross-protection at the population level. From an evolutionary perspective, selection of immune mechanisms allowing for partially nonspecific AIID would appear to be advantageous against highly polymorphic and rapidly evolving pathogens. This new emerging paradigm may have several important consequences on our understanding of individual infectious disease susceptibility and our conception of tolerance, vaccination and therapeutic strategies against infection and cancer. It also underscores the importance of viewing the microbiota and persisting infectious agents as integral parts of the immune system.

http://journal.frontiersin.org/article/10.3389/fmicb.2015.01525/full

 

  • Generation of individual diversity: a too neglected fundamental property of adaptive immune system:

The fitness gains resulting from development of the adaptive immune system (AIS) during evolution are still the subject of hot debate. A large random repertoire of antigenic receptors is costly to develop and could be the source of autoimmune reactions. And yet, despite their drawbacks, AIS-like systems seem to have been independently acquired in several phyla of metazoans with very different anatomies, longevities, and lifestyles. This article is a speculative attempt to explore the selective pressures, which favored this striking convergent evolution. It is well known that the AIS enables an organism to produce a specific immune response against all natural or artificial antigenic structures. However, it is frequently neglected that this response is highly variable among individuals. In practice, each individual possesses a "private" adaptive immune repertoire. This individualization of immune defenses implies that invasion and escape immune mechanisms developed by pathogens will certainly not always be successful as the specific targets and organization of the immune response are somewhat unpredictable. In a population, where individuals display heterogeneous immune responses to infection, the probability that a pathogen is able to infect all individuals could be reduced compared to a homogeneous population. This suggests that the individual diversity of the immune repertoire is not a by-product of the AIS but of its fundamental properties and could be in part responsible for repeated selection and conservation of the AIS during metazoan evolution. The capacity of the AIS to improve the management of cooperative or parasitic symbiotic relationships at the individual level could be a secondary development due to its progressive integration into the innate immune system. This hypothesis constitutes a new scenario for AIS emergence and explains the selection of MHC restriction and MHC diversification.

http://journal.frontiersin.org/article/10.3389/fimmu.2014.00208/full

 

  • Redefining the Immune System as a Social Interface for Cooperative Processes:

Viewed from a neo-Darwinian perspective, the main function of the metazoan immune system (IS) is to insure host integrity against invading microorganisms, which are only considered as selfish competitors that reduce the host's resources, inflict tissue damage, and ultimately compromise host fitness. Coevolution of the host and these competitors has been described as a perpetual arms race (known as the Red Queen hypothesis, Van Valen). This vision implicitly suggests that “The IS evolved under selective pressure imposed by infectious microorganisms” (Janeway) and that the ultimate objective of the IS is to conserve the integrity and sterility of the host. In fact, numerous observations from microbiology and ecology have challenged this paradigm and suggest that infectious organisms and the IS play a crucial, unexpected role in evolution. I propose that the innate and adaptive metazoan IS has evolved under selective pressure favoring symbiosis, a source of genetic diversity, HGT, and cooperation that globally promote better adaptation to selective pressure. In this view, the metazoan IS appears to be responsible for: (i) management of the cooperation of syngeneic cells, which may explain the numerous functions of the IS in the development and maintenance of organisms in the absence of infection; (ii) detection of selfish/cheater behavior of syngeneic or allogeneic cells; and (iii) elimination and memorization of cheaters. This invites reinterpretation of the condition for IS activation. The “danger signal” proposed by Matzinger could be redefined as “selfish/cheater signals.” The importance of selfish/cheater behavior in activation of the IS is demonstrated by the ability of the IS to tolerate our allogeneic cooperative microbiota and fight syngeneic selfish cells (tumors). The crucial importance of infections for the evolution/adaptation of life and maintenance of the fitness of consortia strongly suggests that complete neutralization of infection by immune systems cannot be favorable to host adaptation. Consequently, I propose that vertebrate IS must partially tolerate selfish/cheater/infectious organisms. Only cheaters strongly affecting the fitness of consortia must be eliminated. This could explain the fact that all organisms are, in natural conditions, always infected. These infections are not the consequence of failure of the immune system but a logical consequence of the necessity to partially tolerate infectious organisms, a source of HGT, new potential cooperative partners, etc. This is in total opposition to the classical view of the IS, considered only as a defense mechanism conferring “sanctuary status” on the organisms and obsessed with the eradication of infection and host sterility.

http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003203