Monkeypox Virus Infection of Rhesus Macaques Induces Massive Expansion of Natural Killer Cells but Suppresses Natural Killer Cell Functions

Abstract

Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results showed that the absolute number of total NK cells in the blood increased in response to MPXV infection at a magnitude of 23-fold, manifested by increases in CD56+, CD16+, CD16-CD56- double negative, and CD16+CD56+ double positive NK cell subsets. Similarly, the frequency and NK cell numbers in the lymph nodes also largely increased with the total NK cell number increasing 46.1-fold. NK cells both in the blood and lymph nodes massively proliferated in response to MPXV infection as measured by Ki67 expression. Chemokine receptor analysis revealed reduced expression of CXCR3, CCR7, and CCR6 on NK cells at early time points (days 2 and 4 after virus inoculation), followed by an increased expression of CXCR3 and CCR5 at later time points (days 7-8) of infection. In addition, MPXV infection impaired NK cell degranulation and ablated secretion of interferon-γ and tumor necrosis factor-α. Our data suggest a dynamic model by which NK cells respond to MPXV infection of rhesus macaques. Upon virus infection, NK cells proliferated robustly, resulting in massive increases in NK cell numbers. However, the migrating capacity of NK cells to tissues at early time points might be reduced, and the functions of cytotoxicity and cytokine secretion were largely compromised. Collectively, the data may explain, at least partially, the pathogenesis of MPXV infection in rhesus macaques.

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

“…Cytotoxic lymphocytes such as CD8+ T lymphocytes and NK cells are necessary for the control of viral infections (17)(18)(19)(20), and the functional exhaustion of these cells is correlated with disease progression (29,30). On the other side, exaggerated or not controlled immune responses can be responsible for the organ damage that sometimes accompanies the infection (16,21).…”

“…Natural killer (NK) cells exert the primary control during acute viral infection, but cytotoxic CD8+ T lymphocytes (CTLs) are critical for long-term surveillance (17)(18)(19)(20). The antiviral effects of NK and CD8+ T cells can be mediated by direct cytotoxicity or through the release of IFN-γ.…”

Monkeypox Virus in Nigeria: Infection Biology, Epidemiology, and Evolution

“…According to Song et al, MPXV infection is responsible for changes in the number of lymphocytes including NK cells in NHPs, and lymphadenopathy, as well as lymphoid depletion, in MPXV-challenged NHPs, is a result of MPXV infection [127]. At the end of an experiment conducted by Townsend et al, using Prairie dogs as models, there was a significant increase in the following: the number of all NK subsets at day seven postinoculation, CD16− CD56−, CD16+, CD56+, and CD16+CD56+ NK cells.…”

Non-Human Primate Models of Orthopoxvirus Infections

“…Interestingly, MPXV infection induces a reduced migrating capacity of NK cells and a reduced degranulation capacity. Thus, cytotoxic effects of cytokines were not reached [41].…”