Mechanisms of macrophage manipulation by pathogenic SFG rickettsia: role of mitochondrial and immune pathways

The National Institute of Allergy and Infectious Diseases awarded Old Dominion University $1.322 million in funding on April 10, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate mechanisms by which pathogenic Rickettsia species manipulate macrophage mitochondrial function and evade host immune responses.

The award funds two research aims: determining how pathogenic spotted fever group rickettsia remodel mitochondrial dynamics in macrophages through infection studies, microscopy analysis of mitochondrial morphology, flow cytometry and qPCR-based functional assays, genetic and pharmacological perturbations targeting mitochondrial fusion and fission proteins (MFN1/2, DRP1, OPA-1), and mitochondrial proteomics; and defining regulation of rickettsia-induced interferon responses at the mitochondrial level through selective disruption of RIG-I-like receptor pathway components, measurement of interferon and inflammatory cytokine responses, analysis of ubiquitination and phosphorylation in signaling proteins, RNA immunoprecipitation and sequencing to identify pathogen-associated molecular patterns, and functional assays assessing artificial RIG-I/MDA5 activation effects on rickettsia growth. The research addresses fundamental gaps in understanding how pathogenic rickettsia species achieve dramatic differences in virulence compared to non-pathogenic species and how they sustain viable intracellular niches while evading innate immune defenses.

Performance occurs in Norfolk, Virginia through March 31, 2028. George Mason University serves as a sub-grantee, collaborating on the immune evasion research pathway components.

Abstract

Rickettsiae are obligate intracellular bacteria transmitted by arthropods. Many rickettsiae are pathogenic to humans, causing infections that range from severe, as is the case of rocky mountain spotted fever (r. Rickettsii), mediterranean spotted fever (r. Conorii), or epidemic typhus (r. Prowazekii), to mild, such as those caused by r. Parkeri or r. Africae. In contrast, others have not been associated with disease (e.g., r. Montanensis). What underlies these dramatic differences in pathogenicity among rickettsiae is still not known. Growing evidence provided by US and others has led to the emerging hypothesis that macrophage permissiveness to rickettsial infection acts as a key virulence factor and a strategy employed by pathogenic rickettsia to escape host immune defenses, and promote organ colonization. However, fundamental gaps in knowledge remain regarding the molecular details governing rickettsia-macrophage interactions and how induced alterations contribute to immune evasion. Rickettsiae are strictly dependent on host nutrients/metabolites to survive and proliferate. This massive burden must require tight control of host metabolic/proteostatic systems. Our data points to mitochondria as a central hub used by rickettsia to sustain a viable niche. We hypothesize that pathogenic SFG rickettsia target macrophage mitochondrial function, acting both as clients - through the generation of metabolites, ATP, and transporters actively required by rickettsia - as well as regulators, by redirecting host metabolism-dependent signaling to sustain a viable niche and fine-tune immune defenses to evade innate immunity. We will address our hypothesis with 2 aims: 1. To determine how pathogenic SFG rickettsia remodel mitochondrial dynamics in macrophages; and 2. To define regulation of rickettsiae-induced interferon responses at the mitochondria. In aim 1, we will determine how highly pathogenic (r. Conorii) and mildly pathogenic (r. Parkeri) differentially modulate mitochondrial dynamics through the evaluation of the different components of the fusion/fission machinery. In aim 2, we propose to determine the mechanism(s) by which highly pathogenic (r. Conorii) and mildly pathogenic (r. Parkeri) differentially regulate interferon responses at the mitochondria and modulate innate immune signaling. Innovation: (1) mitochondrial fusion is a still unclear and uncommon response to infection. We propose that pathogenic SFG rickettsia target mitochondria by stimulating fusion by an as-of-yet unknown mechanism, and this will reveal a new "achilles heel" in infection. (2) we propose that pathogenic SFG rickettsia evade immune surveillance through differential regulation of RLR/mavs signaling, a key antiviral defense.