Abstract
Post-acute infection syndromes (PAIS) follow viral syndromes including post-acute sequelae of COVID19 (PASC) which complicates 10-25% of SARS-CoV-2 infections. These syndromes lack precise explanatory mechanisms. We studied 173 human saliva proteomes during respiratory viral syndromes, seeking associations between 44 clinically-relevant protein expression patterns and subsequent sequelae counts. Exploratory models adjusted by extensive clinical annotations found interactions between 23 acutely-responsive proteins and SARS-CoV-2 infection that inversely predicted subsequent neurocognitive sequelae. An overlapping 19 acutely-responsive proteins during any acute respiratory viral syndrome inversely predicted general fatigue-related sequelae. Altogether, 29 proteins, derived from interferon stimulated genes (ISG), were uniformly beneficial, including 13 predictive of both neurocognitive and general sequelae. The proteins suggested both shared early pathobiology and virus-specific protective responses that shaped resolution of acute disease and different PAIS. Acutely elevated protective ISG proteins associated with reduced post-viral symptoms identify investigational starting points for novel mechanisms, diagnostics and therapeutics for PASC and PAIS.
Competing Interest Statement
Theodore G. Liou, Judy L Jensen and Kristyn A Packer received research funding from Anagram, Aridis, BioMX, Calithera, Clarametyx, Gilead, Insmed, Laurent, Novartis, the US Cystic Fibrosis Foundation′s Therapeutic Development Network and Vertex for performance of clinical studies during the study period. Bricelyn H Strauch maintains the copyright for Figure 3. Theodore Liou and Frederick Adler, through the University of Utah, are named as inventors on the following patent applications related to the proteins identified in this manuscript: (1) a provisional patent application titled ″DIAGNOSTICS AND TREATMENTS FOR ACUTE AND POST-VIRAL DISEASE BASED ON INNATE IMMUNE RESPONSES TO SARS-COV-2 INFECTION,″ serial number 63/792,687, filed 4/22/2025; (2) a provisional patent application titled ″ADDITIONAL INNATE IMMUNE RESPONSES WITH DIAGNOSTIC AND TREATMENT POTENTIAL FOR POST-ACUTE SEQUELAE OF COVID19 SYNDROME AND FOR POST-ACUTE INFECTION SYNDROME,″ serial number 63/979,883, filed 2/10/2026; (3) a Patent Cooperation Treaty (PCT) application titled ″METHODS FOR PREDICTING POST-ACUTE SEQUELAE OF VIRAL INFECTIONS USING INTERFERON STIMULATED GENE PROTEINS,″ serial number PCT/US2026/024520, filed 4/21/2026, which incorporates subject matter from (1) and (2); and (4) a provisional patent application titled ″ADDITIONAL ACUTELY EXPRESSED PROTEINS PROTECTIVE AGAINST NEUROCOGNITIVE AND GENERAL POST-VIRAL SEQUELAE,″ serial number 64/102,461, filed 6/30/2026. The applicant on all applications is the University of Utah.
Source:
Link: https://www.medrxiv.org/content/10.64898/2026.08.27.26361488v1
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