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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.

Rhesus monkeys inoculated intravenously with Rift Valley fever (RVF) virus presented clinical disease syndromes similar to human cases of RVF. All 17 infected monkeys had high-titered viremias but disease ranged from clinically inapparent to death. Three (18%) RVF virus-infected monkeys developed signs of hemorrhagic fever characterized by epistaxis, petechial to purpuric cutaneous lesions, anorexia, and vomiting prior to death. The 14 remaining monkeys survived RVF viral infection but, 7 showed clinical signs of illness characterized by diminished food intake, cutaneous petechiae, and occasional vomiting. The other 7 monkeys showed no evidence of clinical disease. All monkeys had detectable serum interferon 24-30 h after infection, but 4 of 7 monkeys that did not develop clinical illness had serum interferon titers within 12 h after infection. In lethally infected macaques, indices of hepatic function and blood coagulation were abnormal within 2 days, implicating early pathogenetic events as critical determinants of survival. Serum transferase values were elevated in proportion to severity of clinical disease and outcome of infection. Both myocardial damage and laboratory evidence consistent with disseminated intravascular coagulation were present in fatal infections. All surviving monkeys developed neutralizing antibodies to RVF virus 4-7 days after infection, and this coincided with termination of viremia. Two fatally infected monkeys were viremic until death on days 6 and 8, and the third cleared viremia on day 5 and developed antibody on day 6 but died on day 15. There was a significant correlation between a delayed interferon response and mortality, suggesting that the early appearance of interferon was influential in limiting the severity of disease.

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