Host regulatory interactions with Moraxella catarrhalis: emerging hypotheses on microRNA networks, extracellular vesicle RNAs, and phasevarions-mediated epigenetics in respiratory pathogenesis.

BACKGROUND: Moraxella catarrhalis is a Gram-negative opportunistic pathogen of the human respiratory tract, historically considered a commensal but now established as a leading cause of otitis media in children and acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults. While phylogenomic studies have revealed two deeply divergent evolutionary lineages, Sero resistant (SR) and Sero sensitive (SS), with distinct virulence and resistance profiles, the molecular dialogue between this bacterium and its host remains incompletely understood. OBJECTIVE: This review moves beyond traditional virulence factor enumeration to explore emerging frontiers in host-pathogen interaction at the RNA and epigenetic levels. We critically synthesize recent advances in three areas: (i) potential manipulation of host microRNA networks by M. catarrhalis and its extracellular vesicles, (ii) the hypothesized role of bacterial small RNAs in interkingdom communication and immune modulation, and (iii) epigenetic regulatory mechanisms, including phasevarions and DNA methylation, that govern phenotypic heterogeneity and vaccine evasion. PROPOSED FRAMEWORK: We propose a mechanistic model wherein M. catarrhalis may actively reprogram host gene expression post-transcriptionally and exploit epigenetic phase-variation to evade immunity. However, we emphasize that much of this model remains hypothetical; direct experimental evidence in M. catarrhalis is currently limited. By integrating findings from transcriptomic profiling, extracellular vesicle biology, and epigenetics, we provide a contemporary framework that reframes M. catarrhalis not as a passive opportunist but as a potential active manipulator of host cellular machinery, a hypothesis that requires rigorous testing. We identify critical knowledge gaps, propose mechanistic models for miRNA-mediated pathogenesis, and outline priority areas for therapeutic and preventive intervention.