Microbiology and Immunology Discipline

Our previous research into the causes of suboptimal humoral immune responses during malaria has led to several key findings, both published and unpublished: (i) Plasmodium infection is linked to hemolytic anemia and splenic hypoxia, (ii) hemolysis- associated phosphatidylserine (PtS) serves as a molecular signal driving the accumulation of effector (EF) short-lived plasmablasts (PBs), (iii) these EF short-lived PBs impair the anti-Plasmodium immune response by acting as a ‘nutrient sink,’ (iv) Axl-/- B cells show impaired differentiation into EF short- lived PBs, and (v) blocking PtS binding during Plasmodium infection reduces the accumulation of these
immunosuppressive PBs and enhances the germinal center response. This project is aimed at exploring key molecular targets and signaling pathways driven by AXL that may modulate humoral immune response against parasitic infections. Successful completion of this project will have broader implications for other diseases where hemolytic anemia and associated plasmablasts accumulation have been reported, including but not limited to COVID-19, Trypanosomiasis, and Dengue. This project is funded by NIH.

In this project, we build on our recent study that immunomodulatory
interventions altering CD4 T cell differentiation imprint a unique transcriptional and epigenetic program on B cells, generating MBCs of extra follicular (EF) origin with superior recall potential.
Using conditional knockout models combined with biochemical, genetic, and multi-omics approaches, we will dissect mechanisms that will bolster humoral immune memory against Plasmodium.

We hypothesize that CD4 T cell–intrinsic EOMES expression is sufficient to drive the generation of extrafollicular MBCs with superior recall potential by inducing IL-9R expression in activated B cells through the IFNγ-T-BET axis.
This hypothesis is based on our published and unpublished findings as summarized here: (i) exogenous ligation of 4-1BB using an agonistic monoclonal antibody (3H3) in Plasmodium-infected mice delays effector humoral immune response but provides enhanced memory-mediated protection from repeat infections, (ii) 3H3 treatment induces robust expression of EOMES in CD4 T cells; conditional deletion of Eomes restores the effector response but reverses the observed memory-mediated protection (iii) exogenous 4-1BB ligation generates fewer MBCs but with markedly enhanced recall potential (iv) these MBCs appear to have an EF origin and depend on B cell-intrinsic T-BET expression; and (v) which drives the expression of IL-9R expression in an IFNg and T-BET dependent manner. Our aims listed below and as illustrated in Fig 1 will attempt to address the mechanisms bywhich exogenous ligation of 4-1BB drives the generation of EF-MBCs and determine the role of IFNg- TBET-IL-9R in this phenomenon.

Malaria has been linked to neurocognitive decline, yet the mechanisms underlying malaria-induced neurocognitive decline (MiND) remain poorly understood. Most existing research in immuno-neuroscience focuses on multiple sclerosis (MS), which provides valuable insights into brain immune function but differs fundamentally from MiND because MS is an autoimmune disorder, whereas MiND arises from parasitemia and infection-driven inflammation. In addition, findings from MS mouse models are difficult to extrapolate to human disease, further widening the gap between our understanding of neuroimmune responses in MS and those that occur in MiND. Current MiND research
therefore relies heavily on cerebral autopsies from affected patients or on mouse models that, similar to MS, have limited translational relevance to the human neuro-immune system. This project focuses on identifying the immune parameters that may contribute to MiND, aiming to bridge these knowledge gaps and advance mechanistic understanding of the disease.

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