The Natural Killer Cell Landscape in the Natural History of Hantavirus Cardiopulmonary Syndrome in a Chilean Cohort.

Hantavirus cardiopulmonary syndrome (HCPS) caused by Andes Orthohantavirus (ANDV) carries case-fatality rates up to 40%; however, the innate immune determinants of disease severity remain poorly defined. Natural killer (NK) cells are central mediators of early antiviral immunity, but their landscape during the earliest phase of ANDV infection has not been characterized. Using multiparameter flow cytometry and unsupervised UMAP-based clustering in PBMCs from 13 HCPS patients stratified by severity and nine healthy donors, we show that severe HCPS is characterized by a coordinated disruption of the CD56dim NK cell compartment, encompassing reduced subset frequencies, specific reduction in the terminally differentiated NKG2C+CD57+ adaptive-like pool, and intrinsic impairment of IFN-γ production and degranulation, deficits that were absent in mild patients and persisted in part beyond clinical recovery. Furthermore, CD56dimCD16+ NK cell frequencies correlated negatively with viral load across all acute patients, independent of clinical severity. These findings establish severe HCPS not merely as a state of NK cell depletion, but as one of selective functional impairment of the most cytotoxically competent NK cell population during the critical early acute phase of ANDV infection.