Extramedullary Megakaryocytes in the onset of Emerging MAYV/CHIKV post-acute infection syndromes

"Post-Acute Infection Syndromes (PAIS) are chronic, debilitating diseases established after the acute phase of infectious diseases. Although known for many decades, PAIS is still poorly understood, the mechanisms of PAIS pathogenesis are largely unexplained and must be tackled to restore the quality of life and productivity of individuals suffering from this condition. Mayaro (MAYV) and Chikungunya (CHIKV) are alphaviruses transmitted to humans via mosquitos, endemic in tropical regions of the globe with an evident potential of emergence in Europe. Both MAYV and CHIKV are the causative agents of diseases characterized by a high incidence of rheumatic complications, such as arthritis and myalgia, which can progress to highly debilitating post-acute infection syndromes that may persist for months or years in about 20-40% patients, causing physical and even mental health disability, and impacting in the population quality of life. The mechanisms involved in PAIS development after MAYV or CHIKV infection are elusive and no specific therapy to treat these diseases is available. Immune cell-mediated inflammation and viral reservoirs are central players in the process, with myeloid immune cells infiltrating tissues such as liver and joints. Team A (P1, F REAL) and Team B (P2, A DA POIAN) decided to join forces to investigate MAYV/CHIKV PAIS cellular/molecular mechanisms, after P2's team B - with more than 20 years of experience with arboviruses such as MAYV, CHIKV, DENV, ZIKV - observed that the liver of MAYV-infected mice is enriched in myeloid progenitors and megakaryocytes (MK). P1's team A is currently investigating the participation of MK as players in PAIS and as host cells for persistent viruses such as HIV-1 and (potentially) SARS-CoV-2. MK are giant polyploid cells from myeloid lineage found in the bone marrow and responsible for the formation of platelets, blood components essential for blood clotting and wound healing. MK also respond to pathogens and inflammatory signals like bona fide immune cells, acting as an immune regulatory cell in viral infections. MK can also exit the bone marrow and lodge in other tissues - called extramedullary MK - but their role when residing in or when entrapped in the microvasculature of other organs is less clear. Under chronic diseases or stress conditions like acute infection MK are found in higher frequencies as compared with non-infected individuals in brain, lung, heart, heart, spleen, liver. And other organs. We hypothesize that MAYV/CHIKV impair MK locally in the bone marrow, generating thereafter immune-trained (reprogrammed) extramedullary inflammatory MK that are inflammatory and fibrogenic, immunologically dysfunctional and collateral products of acute infection. These MK will lodge in different organs and tissues, potentially fueling a tissular reservoir of alphaviruses, damaging tissues and compromising organ functions in line with the multiorgan nature of post-infection syndromes. Strategies targeting extramedullary MK factors (e.g. CXCR4) will be proposed in in vivo models, with the aim of establishing and tackling the immunological/molecular mechanisms involving MKs in MAYV/CHIKV PAIS."