A detoxified E. coli heat-labile toxin LTh(αK) as a mucosal immunomodulator against acute respiratory viral infection: Proof-of-concept in a SARS-CoV-2 rodent model.
Abstract
Background
Acute respiratory viral infections remain a global health burden, and current vaccines induce limited mucosal immunity at the respiratory epithelium. Host-directed strategies that strengthen innate mucosal responses may offer broader protection. LTh(αK), a genetically detoxified E. coli heat-labile toxin with established adjuvant safety, was evaluated for its capacity to enhance mucosal immunity and mitigate respiratory viral injury, using SARS-CoV-2 as a representative challenge model.
Methods
LTh(αK) was tested as a mucosal vaccine adjuvant and as a host-directed immunotherapy. C57BL/6 mice received an intranasal LTh(αK)-adjuvanted SARS-CoV-2 spike protein (S2P) vaccine; serum IgG and IgA and Th1/Th2 cytokines were measured. Syrian golden hamsters received intranasal LTh(αK) after viral challenge, with assessment of clinical parameters, viral titers, histopathology and cytokine transcription.
Results
As an adjuvant, LTh(αK) increased S-specific serum IgG and IgA and Th1 and Th2 cytokine levels. As immunotherapy, LTh(αK) attenuated infection symptoms but did not significantly reduce virus titers at any site or time point, while significantly increasing interferon-beta (IFNβ) transcription in the cranial lung lobe. Overall histopathological lesion scores were significantly lower in LTh(αK)-treated animals at 3 days post-challenge (dpc), a difference not sustained at 5 or 7 dpc. Ultrastructural examination additionally showed increased monocyte activation and reduced mucin production, hemorrhage and lung parenchyma destruction.
Conclusion
LTh(αK) enhanced Th1/Th2 balanced humoral immunity, including S-specific serum IgA, and attenuated early lung injury without reducing viral burden. These proof-of-concept findings support LTh(αK) as a candidate host-directed mucosal immunomodulator for acute respiratory viral infections and warrant further evaluation of its translational potential.