(S-021) Development of a Physiologically Based Infection Kinetic Model to Assess Bacterial Clearance by Various Immunocompromised Mouse Strains Used as Infection Models for Mycobacterium abscessus

Hyunseo Park – Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN; Camron Pearce – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Ilham Alshiraihi – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Ha Lam – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Anthony Hickey – Technology Advancement and Commercialization, RTI International, Durham, NC; Sara Maloney – Technology Advancement and Commercialization, RTI International, Durham, NC; Andres Obregon – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Mercedes Gonzalez-Juarrero – Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO; Bernd Meibohm – Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN

Objectives: Mycobacterium abscessus (Mab) is an opportunistic pathogen with rising prevalence and mortality, posing a growing public health threat. As the host immune status plays a critical role in controlling Mab infections, a quantitative understanding of immune-mediated bacterial clearance is essential for accurate drug efficacy evaluation and therapeutic design. However, dissecting the role of individual immune cell types is challenging due to the complexity of the immune system.

Methods: Here, we applied a physiologically-based mathematical model to infection kinetics from in vivo mouse models with selectively impaired immune functions. This approach enabled quantification of bacterial clearance by specific immune cell populations and revealed organ-specific dissemination patterns across models.

Results: Our findings highlight the critical role of neutrophils in Mab clearance, and the importance of their immunological homeostasis in preventing opportunistic infections. The model-based approach identified the NSG mouse model characterized by the most sustained infection profile due to the absence of mature B and T cells, macrophages and NK cells, combined with intratracheal inoculation as an optimal in vivo model for assessing Mab antibacterial efficacy.

Conclusions: This framework provides a mechanistic foundation for improving therapeutic strategies against Mab and other opportunistic pathogens.

Citations: [1] Dartois V, et al. Preclinical murine models for the testing of antimicrobials against Mycobacterium abscessus pulmonary infections: Current practices and recommendations. Tuberculosis (Edinb) 147 102503. (2024)
[2] Silva MT. When two is better than one: macrophages and neutrophils work in concert in innate immunity as complementary and cooperative partners of a myeloid phagocyte system. J Leukoc Biol 87 93-106. (2010)

Keywords: Infection Kinetics, PBPK, Innate Immune System