Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY Arboviruses maintained in a human-mosquito-human transmission cycle are responsible for fueling periodic outbreaks worldwide and are an increasing public health threat. A critical feature of arbovirus transmission cycles, and a major determinant of their geographic spread and pathogenesis, is the magnitude and duration of viremia in vertebrate hosts. However, few studies have investigated the molecular determinants of viremia. Recent studies published by the Morrison laboratory demonstrated that the murine scavenger receptor MARCO on liver macrophages removes chikungunya (CHIKV) particles and other arthritogenic alphaviruses, including Ross River (RRV) and o’nyong ‘nyong (ONNV) viruses, from murine circulation due to recognition of the lysine (K) residue at position 200 of CHIKV and ONNV E2 glycoprotein and 251 of RRV E2 glycoprotein. My preliminary studies further revealed that CHIKV clearance is also abrogated when mutations were introduced at glutamate (E)208 of E2 and K61 of E1 glycoproteins, and mass spectrometry analysis of the biochemical features important for viral clearance suggested that E1 K61 is methylated. Further analysis of position 208 of CHIKV E2 glycoprotein revealed the importance of a negative charge at this position for CHIKV removal from circulation. As a pattern recognition receptor, MARCO recognizes modified self and non-self molecules, and polymorphisms in human MARCO can predispose carriers to infectious diseases such as tuberculosis. Because the scavenger receptor cysteine-rich (SRCR) domain of MARCO is a binding site for endogenous ligands, such as modified low-density lipoprotein, I hypothesize that the SRCR domain of MARCO stably and noncovalently interacts with an exposed interface between the E1 and E2 glycoproteins of CHIKV, allowing for the removal of viral particles from circulation and a reduction in both the magnitude and duration of viremia. In Aim 1, I will define the residues and biochemical features of CHIKV important for MARCO-dependent clearance from circulation by manipulating surface features of virus particles, assessing how specific mutations impact viral dissemination, and identifying post-translational modifications at specific sites in the E1 and E2 glycoproteins. In Aim 2, I will elucidate the sites on MARCO responsible for binding arthritogenic alphaviruses with cell-based and biochemical approaches. In addition, I will determine the extent to which virus particles interact with human MARCO, and whether known polymorphisms in MARCO affect virus-MARCO interactions, viremia, or clinical outcomes. Taken together, by defining the molecular mechanism of interaction between MARCO and CHIKV, this proposal could provide insights into factors that influence alphaviral pathogenesis, elucidate the relationship between MARCO polymorphisms and viremia, and identify individuals or populations with an increased susceptibility to severe alphaviral infections and outbreaks, respectively.
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