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Front Immunol
. 2025 Nov 5:16:1701728.
doi: 10.3389/fimmu.2025.1701728. eCollection 2025. Hookworm infection modulates lung and intestinal transcriptomic responses to SARS-CoV-2 in Syrian hamsters
Bruce A Rosa # 1 , Mahdiyeh Bigham # 1 , Tamarand L Darling # 1 , Ashutosh Arun 1 , Kumar Sachin Singh 1 , John Martin 1 , Adrianus C M Boon # 1 2 3 , Makedonka Mitreva # 1 4 5
Affiliations
Background: Helminth infections are widespread in resource-limited settings, and modulate host immune responses, with potential implications for viral coinfections. Intestinal helminths can alter susceptibility to respiratory viruses, but the mechanisms influencing SARS-CoV-2 infection outcomes remain poorly understood.
Methods: Using the Syrian hamster model, we investigated the impact of prior infection with the human hookworm Ancylostoma ceylanicum on host responses to SARS-CoV-2. Tissue-specific transcriptional responses were compared among four groups: naive, hookworm-only, SARS-CoV-2-only, and coinfected with both pathogens, 3 and 6 days post-viral infection. Viral titers and weight loss were assessed, and RNA-seq transcriptome profiles from lung and intestinal tissues were interrogated to identify differentially expressed genes and cellular pathways.
Results: Prior hookworm infection did not significantly alter viral titers or weight loss compared to SARS-CoV-2 infection alone, but distinct transcriptional signatures compared were identified compared to either single infection. Coinfection uniquely differentially regulated hematopoiesis and B cell-associated genes (e.g., ATF5, IGHM, JCHAIN) in the lungs, and immune and stress response pathways and inflammation-associated genes (e.g. FOLR2, PLA2GF, FABP3) in the intestine. Genes and pathways differentially regulated by SARS-CoV-2 alone, but with attenuated transcriptional responses in the lungs of coinfected hamsters were observed, including the loss of upregulation of toll-like receptor signaling and previously proposed host biomarkers for COVID-19 severity (CHI3L1, HMOX1), Long COVID (FCG4/FCGR3A and FST) and mortality (FST). In the intestine, hookworm-associated suppression of type I interferon-related genes (TAP1, IRF7) was reversed with SARS-CoV-2 coinfection, highlighting pathogen-specific modulation of innate antiviral signaling. Genes and pathways consistently differentially regulated by with SARS-CoV-2 were consistent with expectations, and many hemoglobin pathways were differentially regulated with hookworm in the intestine. CIBERSORT analysis was estimated relative leukocyte abundances in each sample cohort.
Conclusion: Our findings demonstrate that A. ceylanicum infection reshapes host transcriptional responses to SARS-CoV-2 in a tissue-specific manner, enhancing B cell immunity in the lung while driving intestinal inflammation. Hookworm-induced immune modulation attenuated key SARS-CoV-2-responsive genes and pathways, suggesting potential mechanisms for reduced disease severity observed in helminth-endemic regions. These findings establish a molecular framework to better understand helminth, SARS-CoV-2 and host immune interactions, with relevance for other respiratory viral infections.
Keywords: SARS-CoV-2; coinfection; helminth-virus interaction; hookworm; host response; immune modulation; transcriptomics.
. 2025 Nov 5:16:1701728.
doi: 10.3389/fimmu.2025.1701728. eCollection 2025. Hookworm infection modulates lung and intestinal transcriptomic responses to SARS-CoV-2 in Syrian hamsters
Bruce A Rosa # 1 , Mahdiyeh Bigham # 1 , Tamarand L Darling # 1 , Ashutosh Arun 1 , Kumar Sachin Singh 1 , John Martin 1 , Adrianus C M Boon # 1 2 3 , Makedonka Mitreva # 1 4 5
Affiliations
- PMID: 41268552
- PMCID: PMC12627036
- DOI: 10.3389/fimmu.2025.1701728
Background: Helminth infections are widespread in resource-limited settings, and modulate host immune responses, with potential implications for viral coinfections. Intestinal helminths can alter susceptibility to respiratory viruses, but the mechanisms influencing SARS-CoV-2 infection outcomes remain poorly understood.
Methods: Using the Syrian hamster model, we investigated the impact of prior infection with the human hookworm Ancylostoma ceylanicum on host responses to SARS-CoV-2. Tissue-specific transcriptional responses were compared among four groups: naive, hookworm-only, SARS-CoV-2-only, and coinfected with both pathogens, 3 and 6 days post-viral infection. Viral titers and weight loss were assessed, and RNA-seq transcriptome profiles from lung and intestinal tissues were interrogated to identify differentially expressed genes and cellular pathways.
Results: Prior hookworm infection did not significantly alter viral titers or weight loss compared to SARS-CoV-2 infection alone, but distinct transcriptional signatures compared were identified compared to either single infection. Coinfection uniquely differentially regulated hematopoiesis and B cell-associated genes (e.g., ATF5, IGHM, JCHAIN) in the lungs, and immune and stress response pathways and inflammation-associated genes (e.g. FOLR2, PLA2GF, FABP3) in the intestine. Genes and pathways differentially regulated by SARS-CoV-2 alone, but with attenuated transcriptional responses in the lungs of coinfected hamsters were observed, including the loss of upregulation of toll-like receptor signaling and previously proposed host biomarkers for COVID-19 severity (CHI3L1, HMOX1), Long COVID (FCG4/FCGR3A and FST) and mortality (FST). In the intestine, hookworm-associated suppression of type I interferon-related genes (TAP1, IRF7) was reversed with SARS-CoV-2 coinfection, highlighting pathogen-specific modulation of innate antiviral signaling. Genes and pathways consistently differentially regulated by with SARS-CoV-2 were consistent with expectations, and many hemoglobin pathways were differentially regulated with hookworm in the intestine. CIBERSORT analysis was estimated relative leukocyte abundances in each sample cohort.
Conclusion: Our findings demonstrate that A. ceylanicum infection reshapes host transcriptional responses to SARS-CoV-2 in a tissue-specific manner, enhancing B cell immunity in the lung while driving intestinal inflammation. Hookworm-induced immune modulation attenuated key SARS-CoV-2-responsive genes and pathways, suggesting potential mechanisms for reduced disease severity observed in helminth-endemic regions. These findings establish a molecular framework to better understand helminth, SARS-CoV-2 and host immune interactions, with relevance for other respiratory viral infections.
Keywords: SARS-CoV-2; coinfection; helminth-virus interaction; hookworm; host response; immune modulation; transcriptomics.