Alphaviral infections are foremost in causing debilitating clinical outcomes in humans characterized by rheumatic arthritis like conditions. Though the presence of virus in joints and associated inflammation has been implicated as one of the reasons for the acute and chronic polyarthritis post alphaviral infections, the basis for rheumatic like outcomes is not clear. through an in silico analysis, we have investigated the possibility of an autoimmune process mediated through molecular mimicry in alphaviral infection induced pathogenicity. interestingly, sequence alignment of the structural polyproteins belonging to arthritogenic alphaviruses revealed conserved regions which share homology with human proteins implicated in rheumatoid arthritis (RA). these conserved regions were predicted to exhibit binding to HLA class ii alleles, showcasing their potential to incite t cell help. Molecular docking of the viral peptide and the corresponding homologous region in the human protein onto HLA-DRB1 revealed strong similarities in their binding patterns. Linear and conformational B cell epitope prediction analyses showed that these potential mimics have high propensity to elicit an efficient B cell response. We thus propose that the origin of polyarthritis post-arthritogenic alphaviral infections may also be mediated through a hitherto unknown autoimmune response due to the presence of crossreactive epitopes between viral and human proteins. Alphaviruses belonging to the group IV togoviridae family are positive sense, single stranded RNA viruses. These enveloped viruses are classified as old world and new world. While new world viruses are encephalitogenic, members of the old world are known to induce polyarthritis 1. The members of the old world viruses include Chikungunya Virus (CHIKV), Ross River Virus (RRV), Mayaro Virus (MAYV), O'nyong nyong virus (ONV), Semiliki Forest Virus (SFV) and the Barmah Forest Virus (BFV). These mosquito transmitted viruses are globally distributed and are known to cause acute febrile illnesses, malaise, maculopapular rashes, myalgia, and severe arthralgia in humans 2-5. Most often the infection remains endemic, but some viral strains are also associated with large epidemics such as the Chikungunya virus (CHIKV) outbreak which was spread across 40 countries with 1.4-6.5 million reported cases globally 6. Several studies also report a simultaneous increase in alpha virus associated arthritis lasting even after decrease in viral load 7. While there is a resurgence of alphavirus associated arthritis cases, the knowledge about the molecular level events during infections involved in these conditions and about the direct cause and effect of the phenomenon is very sparse. For instance, macrophages, natural killer cells, CD4+ and CD8+ T lymphocytes have been shown as the main components of the inflammatory cellular infiltrate in animal models of CHIKV and RRV infections 8-10. Production of a broad range of pro-inflammatory cytokines (IL-6, TNF, IFN-α/β, and IFNγ) and chemokines (MCP-1 and RANTES) ...
Underlying mechanisms of multi-organ manifestations and exacerbated inflammation in COVID-19 are yet to be delineated. The hypothesis of SARS-CoV-2 triggering autoimmunity is gaining attention and, in the present study, we have identified 28 human proteins harbouring regions homologous to SARS-CoV-2 peptides that could possibly be acting as autoantigens in COVID-19 patients displaying autoimmune conditions. Interestingly, these conserved regions are amongst the experimentally validated B cell epitopes of SARS-CoV-2 proteins. The reported human proteins have demonstrated presence of autoantibodies against them in typical autoimmune conditions which may explain the frequent occurrence of autoimmune conditions following SARS-CoV-2 infection. Moreover, the proposed autoantigens’ widespread tissue distribution is suggestive of their involvement in multi-organ manifestations via molecular mimicry. We opine that our report may aid in directing subsequent necessary antigen-specific studies, results of which would be of long-term relevance in management of extrapulmonary symptoms of COVID-19.
E. coli has the ability to ferment both C5 and C6 sugars and produce mixture of acids along with small amount of ethanol. In our previous study, we reported the construction of an ethanologenic E. coli strain by modulating flux through the endogenous pathways. In the current study, we made further changes in the strain to make the overall process industry friendly; the changes being (1) removal of plasmid, (2) use of low-cost defined medium, and (3) improvement in consumption rate of both C5 and C6 sugars. We first constructed a plasmid-free strain SSY13 and passaged it on AM1-xylose minimal medium plate for 150 days. Further passaging was done for 56 days in liquid AM1 medium containing either glucose or xylose on alternate days. We observed an increase in specific growth rate and carbon utilization rate with increase in passage numbers until 42 days for both glucose and xylose. The 42nd day passaged strain SSK42 fermented 113 g/L xylose in AM1 minimal medium and produced 51.1 g/L ethanol in 72 h at 89% of maximum theoretical yield with ethanol productivity of 1.4 g/L/h during 24-48 h of fermentation. The ethanol titer, yield and productivity were 49, 40 and 36% higher, respectively, for SSK42 as compared to unevolved SSY13 strain.
Muscle stem cells (MuSCs) experience age-associated declines in number and function, accompanied by mitochondrial electron transport chain (ETC) dysfunction and increased reactive oxygen species (ROS). The source of these changes, and how MuSCs respond to mitochondrial dysfunction, are unknown. We report here that in response to mitochondrial ROS, murine MuSCs directly fuse with neighboring myofibers; this phenomenon removes ETC-dysfunctional MuSCs from the stem cell compartment. MuSC–myofiber fusion is dependent on the induction of Scinderin, which promotes formation of actin-dependent protrusions required for membrane fusion. During aging, we find that the declining MuSC population accumulates mutations in the mitochondrial genome but selects against dysfunctional variants. In the absence of clearance by Scinderin, the decline in MuSC numbers during aging is repressed; however, ETC-dysfunctional MuSCs are retained and can regenerate dysfunctional myofibers. We propose a model in which ETC-dysfunctional MuSCs are removed from the stem cell compartment by fusing with differentiated tissue.
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