• 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 Acinetobacter baumannii infection in mice

Acinetobacter baumannii is a gram-negative aerobic commensal coccobacillus that can cause severe healthcare-associated infections such as hospital-acquired bacterial pneumonia, especially amongst immunocompromised individuals. Its tolerance to desiccation and disinfectants contribute to its persistence in the hospital environment. Although its incidence is lower than for other healthcare-associated pathogens, A. baumannii infections are frequently multidrug resistant (MDR), making them difficult to treat and associated with high mortality. The World Health Organization has placed carbapenem-resistant A. baumannii on Priority 1 ‘‘critical’’ and the number 1 ranked organism recommended for new research and development. It has also been placed in the restrictive list of ESKAPE pathogens (3) and ranked as top priority by the American Centers for Disease Control and Prevention. Given the increasing difficulty in treating A. baumannii infections, there is an urgent need to develop new therapeutic strategies. Immunomodulators that stimulate selectively host innate immune mechanisms have potential as treatment. The risk of rapid development of resistance to innate immune effectors is low and the innate response promotes the development of an adaptive immune response that can protect over the long term. However, the innate response can also generate important pathologies such as cytokine storm. Thus, the development of such therapies requires a better characterized the protective host immune response controlling A. baumannii infection. Our group is working on several different aspects at the interface between the host and A. baumannii in experimental mouse models:

 

  • The identification of immune effector mechanisms implicated in the control of A. baumannii growth in vivo

 

  • The development of candidate vaccines capable of protecting immunocompromised mice against infection by A. baumannii.

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. Brucellosis affects a large range of mammals and is caused by facultative intracellular Gram-negative alphaproteobacteria of the genus Brucella. 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 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.

- MyD88-Dependent Activation of B220CD11b+LY-6C+ Dendritic Cells during Brucella melitensis Infection

https://journals.aai.org/jimmunol/article/178/8/5182/74411/MyD88-Dependent-Activation-of-B220-CD11b-LY-6C

- In situ microscopy analysis reveals local innate immune response developed around Brucella infected cells in resistant and susceptible mice

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1002575

- Crucial role of gamma interferon-producing CD4+ Th1 cells but dispensable function of CD8+ T cell, B cell, Th2, and Th17 responses in the control of Brucella melitensis infection in mice

https://journals.asm.org/doi/10.1128/IAI.00761-12

- Humoral immunity and CD4+ Th1 cells are both necessary for a fully protective immune response upon secondary infection with Brucella melitensis

https://journals.aai.org/jimmunol/article/192/8/3740/93927/Humoral-Immunity-and-CD4-Th1-Cells-Are-Both

- Brucella melitensis invades murine erythrocytes during infection

https://journals.asm.org/doi/10.1128/IAI.01779-14

- In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137835

- Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

https://journals.aai.org/jimmunol/article/196/9/3780/105937/Identification-of-Immune-Effectors-Essential-to

- Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma-Dependent Alterations of Marginal Zone Macrophages in the Spleen

https://journals.asm.org/doi/10.1128/IAI.00115-17

- Route of Infection Strongly Impacts the Host-Pathogen Relationship

https://www.frontiersin.org/articles/10.3389/fimmu.2019.01589/full

- Aconitate decarboxylase 1 participates in the control of pulmonary Brucella infection in mice

https://pubmed.ncbi.nlm.nih.gov/34525130/

 

  • 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).

- Allergic Asthma Favors Brucella Growth in the Lungs of Infected Mice

https://www.frontiersin.org/articles/10.3389/fimmu.2018.01856/full

- Trypanosoma Infection Favors Brucella Elimination via IL-12/IFNγ-Dependent Pathways

https://www.frontiersin.org/articles/10.3389/fimmu.2017.00903/full

 

  • The identification of bacterial genes required to infect and persist in mice.

We used Transposon Sequencing (Tn-Seq) strategy to identify the bacterial genes indispensable to Brucella infection and persistence in mice.

- Genome-wide analysis of Brucella melitensis genes required throughout intranasal infection in mice

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010621

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)

 

Conceptual 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.

 

  • Based on interdisciplinary approach (immunology, microbiology, evolution theory, system theory), I tried to revisiting some dominant paradigms in immunology and evolutionary theory:

- Diversity Generator Mechanisms Are Essential Components of Biological Systems: The Two Queen Hypothesis.

https://www.frontiersin.org/articles/10.3389/fmicb.2018.00223/full

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

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

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

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

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

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

 

  • I also try to participate in a reflection on the regulation of scientific innovations and on the place of scientific knowledge in governance in the face of global threats:

- The Tragedy of Liberal Democratic Governance in the Face of Global Threats

https://www.frontiersin.org/articles/10.3389/fpubh.2022.902724/full

- Ethical control of innovation in a globalized and liberal world: Is good science still science?

https://www.sciencedirect.com/science/article/pii/S0160932719300146?via%3Dihub