Nasal microbiome could be aiding COVID-19 infection

The presence of certain bacteria in the nose appear to contribute to a more receptive environment for SARS-CoV-2 in the respiratory tract, according to new research.

“The nasal microbiome may influence host risk for COVID-19 by modulating the expression of key proteins that facilitate SARS-CoV-2 entry, including angiotensin-converting enzyme 2 (ACE2), which binds the virus, and transmembrane serine protease 2 (TMPRSS2), which activates viral entry into nasal epithelial cells,” the authors said.

In a cross-sectional cohort involving 111 individuals who tested positive for SARS-CoV-2 infection (case) and 342 individuals with a negative test result (control), elevated nasal ACE2/TMPRSS2 expression was indeed associated with up to a more than threefold increase in the risk of contracting COVID-19 compared with no detectable ACE2/TMPRSS2 levels (ACE2 detected or TMPRSS2 Cp ≤32 [high]: adjusted odds ratio [aOR], 3.58, 95 percent confidence interval [CI], 1.71–7.47; ACE2 not detected and TMPRSS2 Cp >32 [medium]: aOR, 2.10, 95 percent CI, 1.03–4.26). [EBioMedicine 2025;doi:10.1016/j.ebiom.2025.105660]

At the high ACE2/TMPRSS2 expression category, men had greater odds of contracting COVID-19 infection (aOR, 4.67, 95 percent CI, 1.51–14.46) compared with women (aOR, 2.70, 95 percent CI, 1.02–7.12), although interaction by sex was not significant (p=0.34). Expression categories did not significantly differ by age (p=0.33).

Longitudinal expression pattern

Additionally, analysis of data from a longitudinal cohort of 97 individuals in the case group and 286 in the control group showed that the case group had distinct longitudinal nasal ACE2/TMPRSS2 expression patterns prior to SARS-CoV-2 infection.

Specifically, the ACE2/TMPRSS2 expression in the case group showed greater variability over time than in the control group (54.4 percent vs 45.8 percent; p=0.029), with more frequent shifts toward higher expression category—from low to medium or high, or from medium to high (42.6 percent vs 22.0 percent; p=0.002). The case group was more likely to have persistently high expression categories across timepoints leading up to the infection (aOR, 1.62; p=0.016).

Nasal microbiome characteristics

Characterization of the nasal microbiome composition in a separate cohort of 428 individuals led to the identification of 13 taxa that predicted nasal ACE2/TMPRSS2 expression, including seven of the eight nasal community state type (CST) indicators.

Nasal ACE2/TMPRSS2 expression was elevated in the presence of high nasal loads of Staphylococcus aureus (3.5–5.9 vs <3.5 log₁₀ gene copies per swab: aOR, 1.85, 95 percent CI, 1.15–2.96; p=0.011), Haemophilus influenzae (≥5.7 vs <5.7 log₁₀ gene copies per swab: aOR, 4.17, 95 percent CI, 1.37–16.16; p=0.014), or Moraxella catarrhalis/nonliquefaciens (≥4.8 vs <4.8 log₁₀ gene copies per swab: aOR, 7.36, 95 percent CI, 2.51–21.63; p<0.001).

Conversely, decreased nasal ACE2/TMPRSS2 expression was observed in the presence of high-density populations of Dolosigranulum pigrum (≥5.7 vs <5.7 log₁₀ gene copies per swab: aOR, 0.57, 95 percent CI, 0.30–1.11; p=0.10).

Targeting nasal bacteria to cut risk

“To our knowledge, our study is the first to report the predictive value of nasal ACE2/TMPRSS2 expression for future SARS-CoV-2 infection,” the authors said.

“We’ve known that the virus SARS-CoV-2 enters the body through the respiratory tract, with the nose being a key entry point. What’s new—and surprising—is that bacteria in our noses can influence the levels of proteins that the virus uses to infect cells,” said senior study author Prof Cindy Liu from the GW Milken Institute School of Public Health in Washington, DC, US.

Liu and colleagues noted that the fact that the nasal microbiome is not genetically determined and can be changed offers a unique opportunity to mitigate COVID-19 risk.

A total of 1,548 self-collected nasal swabs samples from a population-based surveillance testing of community-dwelling adults in Washington DC (cross sectional, longitudinal, and microbiome cohorts) were included in the analysis. Nasal ACE2/TMPRSS2 expression was measured using RT-qPCR, while the nasal microbiome was characterized using 16S rRNA gene-based qPCR and sequencing.