Viral Infection & Chronicity

We investigate whether HIV-1 (and selected RNA viruses) chronically infect hematopoietic stem and progenitor cells (HSPC) and megakaryocyte-biased progenitors, and whether terminally differentiated progeny inherit virus and dysfunction, thereby impairing immune homeostasis and immune reconstitution, in line with previous demonstrations by the team leader and group (J Mol Cell Biol 2024, Sci Trans Med 2020).  Using hiPSC-derived bone marrow organoids, primary human bone marrow and advanced megakaryocyte/platelet models, this axis will (i) map viral reservoirs in defined progenitor subsets, (ii) determine how infection remodels myelopoiesis (including non-canonical megakaryopoiesis and fibrosis), and (iii) evaluate how virus-containing megakaryocytes and platelets fuel peripheral immune injury and limit curative strategies such as HSPC transplantation.

Building on the concept of trained immunity and previous investigations by the team leader on immune-metabolic reprogramming of myeloid HIV reservoirs (Nat Commun 2022) we will first exploit clinically relevant trained immunity inducers to epigenetically educate HSPC and megakaryocyte progenitors toward an antiviral, low-inflammatory profile, aiming at durable reservoir restriction and improved immune restoration in people living with HIV. In parallel, it will investigate how acute infection by SARS-CoV-2, IAV and emerging alphaviruses (MAYV/CHIKV, col. UFRJ-Brazil) imprints megakaryocyte progenitors to generate dysfunctional megakaryocytes that sustain viral persistence, tissue inflammation/fibrosis and hematopoietic aging in PAIS, and test interventions targeting these trained megakaryocytes in murine and human PAIS models.

Platelet membrane-cloaked nanoparticles are proposed as a biocompatible drug delivery platform to target and eliminate persistently HIV-infected cells. By coating antiviral drug–loaded synthetic nanoparticles with platelet membranes, this biomimetic system improves specificity, reduces hemolysis, and enhances biodistribution. Platelet membranes naturally home to inflammatory sites, interact with monocytes and CD4 T cells, and are cleared by tissue macrophages, enabling targeting of both lymphoid and myeloid HIV reservoirs in blood and tissues. This versatile technology could be extended to other chronic viral infections (CIFRE, col. EFS, Centrale Lille).

The gut microbiota plays a critical role in health and disease. Our group has recently patented several therapeutic applications in infections, including compounds produced by the gut microbiota such as short-chain fatty acids (ANR ACROBAT). We have shown that these metabolites attenuate secondary disease outcomes during influenza – including bacterial superinfection (Cell Reports 2020). More recently, we have characterized 3-indole propionic acid (IPA), a tryptophan microbial-derived metabolite, as an antiviral and anti-inflammatory component (Gut Microbes 2024, Start-AIRR IPA-VIR). Pharmacological approaches, next-generation probiotics and postbiotics are being developed. These notably include bacterial strains selected for their strong anti-inflammatory potential and their ability to produce short-chain fatty acids or IPA in symbiosis with specific nutrients (Front Immunol 2024). We have reported the marked impact of influenza and SARS-CoV-2 on gut microbiota’s composition and function (Cell Reports 2020, Infect & Immun 2021, Gut Microbes 2020, 2022a, 2022b). This might be important in the long-term effect of respiratory viral infection.

Aging strongly influences the functionality of the gut microbiota. Our recent data demonstrate the importance of the age-related alteration of the gut microbiota in pulmonary defense against respiratory infection (ANR GUTSY). Moreover, the virus-induced dysbiosis is exacerbated in aged individuals and this likely plays a major part on disease severity (Gut Microbes 2025, Sci Report 2025). In collaboration with B. Lucas (Inst Cochin, Paris), we are investigating how an aged microbiota alters the T cell compartment and contributes to immune responses during influenza infection (MicrobioTaging, France 2030, PEPR SAM).

We have a strong interest in cellular senescence, a biological process that affects cell function. We have recently investigated the role of age-associated, naturally occurring senescent cells, as well as stress- (virus-) induced senescent cells, during experimental influenza and COVID-19 (ANR INFLUENZAGING and SENOCOVID). To this end, we have developed complementary approaches, including pharmacological (senolytic) and genetic strategies (coll S Adnot, Inst Mondor). Our data show that respiratory infection associates with cellular senescence and that this phenomenon is exacerbated in old individuals (Am J Respir Cell Mol Biol 2022, Nature Aging 2023, Aging Cell 2025). Age-related cellular senescence favors the severity of COVID-19 and influenza (Nature Aging 2023, Aging Cell 2025, submitted). In particular, senescent cells are important in mitigating the repair processes that occur in the lungs post-pneumonia. Our objective is to better characterize the nature of senescent cells during infection and to optimize protocols for their selective depletion (SENINFLU, submitted). In addition to our focus on aging in the context of respiratory infection, our laboratory is also investigating how aging alters immune responses following vaccination (France Vaccin 2030).

Aging, the strongest risk factor for severe respiratory infections (including IAV and SARS-CoV-2 infections), is also associated with changes in white adipose tissue (WAT) mass, distribution and function, thereby questioning the role of adipose tissues in the pathophysiology of these diseases. We have shown that influenza infection in young adult mice induces persistent alterations in whole-body glucose metabolism and disrupts the inflammatory and metabolic functions of the WAT, notably through the emergence of thermogenic brown-like adipocytes (Communications Biology 2020). We are currently investigating the role of IAV-induced endoplasmic reticulum stress in infection-associated WAT browning, particularly in aged hosts, in whom the WAT browning capacity is blunted (CPER CTRL 19 FEDER DESTRESS-Flu). In parallel, we reported that SARS-CoV-2 infection in hamsters (young adult and aged) causes significant damage to WAT. Importantly, while these damages are rapidly repaired in young adult hosts, they worsen and persist long term in aged hosts, leading to sustained disruptions in lipid metabolism in the elderly (Cell Death & Disease 2023). Most recently, we demonstrated that the gut-lung-WAT axis is disrupted in aged mice during IAV infection. This breakdown in inter-organ communication and lipid metabolic homeostasis may contribute to the heightened susceptibility of older adults to severe flu complications (Scientific Reports 2025). These findings could pave the way for interventional strategies – such as prebiotics, next-generation probiotics or postbiotics, and targeted lipid-lowering approaches – aimed at restoring the gut-lung-WAT axis and potentially enhance antiviral defenses in older adults.