NK cells are activated and primed for skin-homing during acute dengue virus infection in humans

Abstract

Despite animal models showing that natural killer (NK) cells are important players in the early defense against many viral infections, the NK cell response is poorly understood in humans. Here we analyze the phenotype, temporal dynamics, regulation and trafficking of NK cells in a patient cohort with acute dengue virus infection. NK cells are robustly activated and proliferate during the first week after symptom debut. Increased IL-18 levels in plasma and in induced skin blisters of DENV-infected patients, as well as concomitant signaling downstream of the IL-18R, suggests an IL-18-dependent mechanism in driving the proliferative NK cell response. Responding NK cells have a less mature phenotype and a distinct chemokine-receptor imprint indicative of skin-homing. A corresponding NK cell subset can be localized to skin early during acute infection. These data provide evidence of an IL-18-driven NK cell proliferation and priming for skin-homing during an acute viral infection in humans.

Natural killer cell immunotypes related to COVID-19 disease severity

“…Transiently reduced NK cell numbers during the acute phase of infections have also been shown in SARS-CoV-1 infection (34) and in acute hantavirus infection (13). The magnitude of the present detected NK cell response, with a quarter of the circulating cells either displaying signs of proliferation or activation, mirrors the responses observed during acute dengue fever and in acute hantavirus infection (13,14). The present in-depth phenotypic assessment of NK cells in moderate and severe COVID-19 patients revealed an activated phenotype with up-regulated levels of effector molecules and chemokines, activating receptors, and nutrient receptors.…”

Natural killer cell activation related to clinical outcome of COVID-19

“…NK cells are known to rapidly respond during diverse acute viral infections in humans including those by dengue virus, hantavirus, tick-borne encephalitis virus, and yellow fever virus [13][14][15]32 . Although a similarly detailed analysis of NK cells has not been performed in acute SARS-CoV-2 infection causing COVID-19, early reports from the pandemic have indicated low circulating NK cell numbers in patients with moderate and severe disease 20,21,23 .…”

“…Furthermore, IL-6 associated with Pi3K-Akt and FoxO signaling in NK cells. Both of these pathways are known to coordinate the cell cycle and have previously been reported to be activated in NK cells during acute dengue infection 14 . The analysis also revealed a role for CCL2 in cell cycle regulation, possibly reflecting a shared role for this factor in activation and migration of both NK cells [47][48][49] and myeloid cells 24,25 to the site of infection 50 .…”

“…Evidence for a direct role of NK cells in protection against viral infections comes from patients with selective NK cell deficiencies as these develop fulminant herpesviruses and other infections 11,12 . NK cells have also been shown to rapidly respond during the acute phase of several human infections including infections with hantavirus, tick-born encephalitis virus, influenza A virus (IAV), and dengue virus as well as during live-attenuated yellow-fever vaccination [13][14][15][16] . NK cells not only have the capacity to directly target and kill infected cells but can also influence adaptive T cell responses.…”

Regulation of the human NK cell compartment by pathogens and vaccines

“…Acute dengue virus infection is associated with robust proliferation of all NK cell subsets, irrespective of their differentiation status, although CD56 bright and CD56 dim CD57 − NK cells dominate the response; this is associated with increased IL‐18 concentrations in plasma (and in experimentally induced skin blister fluid) and activation of IL‐18‐induced signalling pathways 54 . In this case, the cells preferentially homing to the skin were CD56 bright and expressed a unique combination of chemokine receptors, including CLA‐1 which is typically associated with skin homing 54 …”