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.
Highlights
Monkeypox virus (MPXV), an emerging virus that could cause up to 10% lethality in humans, poses a risk to human health as an infectious agent and as a potential biological weapon
We report for the first time the kinetics of Natural killer (NK) cell responses to MPXV infection in the rhesus macaque model
We showed that both CD56+ cells and DN cells from blood and lymph nodes (LNs) displayed the highest level of Ki67 expression, and CD16+ cells had little Ki67 expression
Summary
Monkeypox virus (MPXV), an emerging virus that could cause up to 10% lethality in humans, poses a risk to human health as an infectious agent and as a potential biological weapon. Human MPXV infection resembles, in many aspects, clinical symptoms of smallpox, including fever, weight loss, lesions, and death [1,2]. To fully understand the pathogenesis of MPXV and related orthopoxviruses, such as variola virus, and to provide a model to evaluate countermeasures to these poxviruses, a MPXV non-human primate (NHP) model has been developed [3,4]. NHPs infected with MPXV have symptoms resembling those of human monkeypox and smallpox. Intravenous (IV) injection of high doses (~5 x 107 PFU) of MPXV led to 80% lethality in macaques and injection of 5 x 106 PFU of MPXV resulted in survival of most macaques (>80%) [3,4]. While most studies were focused on the pathology and pathogenesis of MPXV, little is known about the innate and adaptive immune responses to MPXV infection in this model
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