Unraveling the complex interplay: immunopathology and immune evasion strategies of alphaviruses with emphasis on neurological implications

Figures

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  Figure 1. Alphavirus induced innate immune response. The innate immune response induced by alphaviruses involves a series of key mechanisms. (1) Alphavirus recognition is mediated by pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs) associated with the invading viruses. This recognition is facilitated by various receptors, including (2) TLR3, TLR7, and TLR8 located in endosomes, as well as (3) RIG-I-like receptors (RLRs) such as RIG-I and MDA5 found in the cytoplasm. These receptors detect viral RNA and initiate antiviral responses by activating signaling cascades that ultimately lead to the activation of transcription factors. (4) NOD-like receptors (NLRs), including NLRP3 and NLRP1, form inflammasomes that activate caspase-1, resulting in the production of pro-inflammatory cytokines IL-1β and IL-18. (5) C-type lectin receptors (CLRs) are also activated during alphavirus infection, playing a role in modulating the immune response. (6) The activation of PRRs triggers signaling cascades that culminate in the activation of transcription factors. This activation leads to the expression of type I interferons (IFNs), IFN-stimulated genes (ISGs), as…

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  Figure 2. Alphavirus immune evassion with emphasis on type I IFN responses. (1) Alphavirus attachment and entry are mediated by host pattern recognition receptors (PRRs), such as RIG, NOD, and TLRs, triggering the production of IFN-I. Once inside the host’s cells, alphaviruses interfere with the IFN-I system at various levels: (2) Inhibition of the cGAS-STING pathway. Following CHIKV infection, there is a significant decrease in cGAS expression, while STING expression remains relatively stable. The non-structural protein nsPl interacts with STING, affecting the activation of IFNs and the activation of the IFN-β promoter, typically controlled by cGAS-STING pathway; (3) CHIKV nsP2 and E1/E2, and SINV nsPI, inhibit the activation of the IFNβ-promoter triggered by the MDA5/RIG-I receptor signaling pathway; (4) The nsP2 from CHIKV, MAYV, SINV, SFV influence ISGs through modifications such as palmitoylation and phosphorylation to hinder interferon α/β and ISG production; (5) Inhibition of JAK-STAT signaling: CHIKV disrupts the phosphorylation of STAT1, essential for IFN-induced JAK-STAT signalling, aiding in immune evasion and enhancing viral replication. (6) Alphaviruses develop viral RNAi…

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  Figure 3. Proposed mechanism of arthritogenic viruses’ pathogensis: from skin entry to neuroinflammation. (1) When a virus-infected mosquito bites a human, it injects saliva containing the virus through its proboscis, breaking the skin barrier. The virus initially infects dendritic cells and fibroblasts, triggering the activation of the innate- immune system through pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and RIG-I type receptors (RLRs). This initiates a series of immune responses, including the recruitment of macrophages and other immune cells, as well as the production of pro-inflammatory cytokines (such as IL-6 and TNF-α), chemokines (CCL2, CXCL10), and interferons (IFN-α. and IFNβ); (2) despite the body’s efforts to contain the virus, it reaches the nearest lymph node with the help of migratory immune cells like dendritic cells. In the lymph nodes, the virus replicates intensely before .entering the bloodstream, causing viremia. From there, the virus spreads to various organs like the liver, muscles, joints, spleen, and, in severe cases, the brain; (3) the virus reaches the brain through peripheral nerves and the bloodstream; (4) once in the Central Nervous…