Disruption in the Host–Phage Dynamics and Altered Microbial Diversity in the Upper Respiratory Tract of SARS-CoV-2-Infected Individuals

Background: The upper respiratory tract (URT) is an important site for the predisposition and multiplication of the SARS-CoV-2 virus. Therefore, URT is a critical site for investigating the changes in the microbiome caused by the SARS-CoV-2 infection. This study aims to compare phageome diversity and investigate the correlation of the phageome profiles with the sample type (SARS-CoV-2 or control) to determine the nature of phage–host interactions in the human URT microbiome and to assess the effect of SARS-CoV-2 viral load on host and phage abundance. Materials and Methods: In this study, we have used the whole-genome shotgun metagenomic approach to investigate URT swab samples ( n = 96) collected from SARS-CoV-2-positive individuals ( n = 48) (nonhospitalized but symptomatic) and healthy controls ( n = 48) belonging to five districts of central India. Results: The results revealed distinct phageome profiles among the groups; Detrevirus dominated the composition in the control samples, while Maxrubnervirus was dominant in SARS-CoV-2 samples. Microbial diversity analysis showed significantly higher richness in the SARS-CoV-2 group compared to controls for both bacteria (Chao1: 886.00 vs. 351.00, p < 0.0001) and phages (Chao1: 39.00 vs. 16.00, p = 0.0002). Bacterial diversity (Simpson index) was lower in the SARS-CoV-2 group (0.88 vs. 0.93, p = 0.0024), whereas phage diversity was higher in the SARS-CoV-2 group (0.86 vs. 0.79, p = 0.0384). Viral load, as reflected by cycle threshold (Ct) values, significantly influenced both bacteria ( H = 6.69, p = 0.035) and phage ( H = 8.97, p = 0.011) abundances. Host–phage interaction networks appeared disrupted in SARS-CoV-2 samples, with a weaker logistic model fit ( R 2 = 0.7425) than controls ( R 2 = 0.9265). Conclusion: SARS-CoV-2 infection alters URT microbiome composition, increasing microbial diversity but disrupting host–phage dynamics. SARS-CoV-2 Viral load correlates with the shifts in microbial abundance, indicating infection-driven shifts in microbiome stability compared to healthy controls.