Immunology of MPXV
MPXV infection elicits both intrinsic and adaptive immune responses in the host. Pathogen-associated molecular patterns (PAMPs) from poxviruses and their envelope or core proteins can be sensed by pattern recognition receptors (PRRs) to initiate a faster but less specific innate immune response [32]. Intrinsic immunity is the host’s first line of defense against poxvirus infection and includes the role of antiviral proteins such as IFN-I, pro-inflammatory cytokines, chemokines, and intrinsic immune cells such as NK cells [24,33–35]. These effector molecules and cells mediate direct antiviral effects or coordinate adaptive immune responses to contain different stages of poxvirus infection. Among them, IFN-I is the hallmark effector of the antiviral response, which interferes with viral replication by mediating viral mRNA degradation and inhibiting translation [36]. NK cells are important players in the host’s innate defense against viral infection and contribute to cell-mediated immunity through cytokine secretion [37]. In addition, in a study of VARV-infected cynomolgus macaques, levels of IFN-γ, IL-8, IL-6, CCL2, and CCL4 were significantly increased during the first four days after infection [38]. In MPXV-infected rhesus monkeys, the number of NK cells in peripheral blood and lymph nodes was significantly increased [39]. The importance of B cells and immunoglobulins against poxvirus can be demonstrated by the successful global vaccination campaign using a live VACV vaccine [40,41]. Cross-reactive VACV-induced immunoglobulins from human vaccines have now been shown to recognize 14 MPXV proteins that have the potential to become antigen-based serodiagnostic tools [42]. In particular, three proteins, A26, D8, and H3, can be targets by neutralizing MPXV antibodies, while proteins A33, A44, and C19 are the major antigens of IgM isolated from macaques in the acute phase of MPXV infection [42]. T cells not only support antibody development but also exert a direct anti-orthopoxvirus effect. Helper T lymphocytes (CD4+ T cells) play a role in promoting the recall and differentiation of memory B cells into antibody-secreting cells [43]. In a mouse model of VACV infection, CD8+ T cells have been shown to eradicate virus-infected monocytes and minimize virus transmission [44]. In addition, IFN-γ secreted by CD8+ T cells has been shown to protect against lethality [45].
Like many viruses, MPXV excels at blocking, evading, and tricking the body’s immune protection in a variety of ways. Here, we briefly discuss some of these mechanisms. MPXV can interfere with the recognition of viral molecules by intrinsic immune cells. Intrinsic immune cells are activated by binding PAMPs through their PRRs. Common PRRs include Toll-like receptor (TLR), NOD-like receptor, RIG-1-like receptor, C-type lectin-like receptor, and cytoplasmic protein kinase receptor [46,47]. Once the PRR binds to a viral molecular ligand, it initiates signaling cascade responses that activate inflammation-related transcription factors such as NF-κB, IRFs, and AP-1 [48]. MyD88, TRIF, and TRAM are intracellular adapter proteins involved in TLR signaling and are essential for triggering intracellular immune responses [49]. MPXV contains genes encoding a variety of proteins, such as protein A47R, which can interact with and impair the function of adaptor proteins, thereby inhibiting the activation of the inflammation-related transcription factors NF-κB and IRF3, resulting in the inability of the intrinsic immune system to recognize the virus [50]. In addition, MPXV inhibits the ability of cells to undergo apoptosis. For example, MPXV may block the activity of caspase-1, caspase-8, and caspase-9, which are essential for apoptosis [50,51]. MPXV also has genes encoding Bcl-2 protein mimetic activity, which play a key role in the regulation of apoptosis [50,52]. MPXV has been shown to evade intrinsic host immunity against viruses by encoding an F3 protein that inhibits multiple steps of IFN signaling [53,54]. MPXV encodes a complement control protein that prevents the initiation of the complement activation pathway [55]. In addition to the above mechanisms, MPXV has several genes encoding proteins that may interfere with cytokine and chemokine production and ubiquitin-proteasome activity, thereby disrupting various stages of the host inflammatory cascade response [50].