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].