Disease progression in mice exposed to low-doses of aerosolized clinical isolates of Burkholderia pseudomallei

Abstract

Mouse models have been essential to generate supporting data for the research of infectious diseases. Burkholderia pseudomallei, the etiological agent of melioidosis, has been studied using mouse models to investigate pathogenesis and efficacy of novel medical countermeasures to include both vaccines and therapeutics. Previous characterization of mouse models of melioidosis have demonstrated that BALB/c mice present with an acute infection, whereas C57BL/6 mice have shown a tendency to be more resistant to infection and may model chronic disease. In this study, either BALB/c or C57BL/6 mice were exposed to aerosolized human clinical isolates of B. pseudomallei. The bacterial strains included HBPUB10134a (virulent isolate from Thailand), MSHR5855 (virulent isolate from Australia), and 1106a (relatively attenuated isolate from Thailand). The LD50 values were calculated and serial sample collections were performed in order to examine the bacterial burdens in tissues, histopathological features of disease, and the immune response mounted by the mice after exposure to aerosolized B. pseudomallei. These data will be important when utilizing these models for testing novel medical countermeasures. Additionally, by comparing highly virulent strains with attenuated isolates, we hope to better understand the complex disease pathogenesis associated with this bacterium.

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

“…In previous murine studies of melioidosis, usually one or two strains of B. pseudomallei were evaluated at the same time [30,31]. Furthermore, we have shown that the BALB/c mouse is very susceptible to infection to all the human clinical strains of B. pseudomallei examined, while the C57BL/6 mouse was significantly more resistant to infection to the same B. pseudomallei strains compared to the BALB/c mouse [29]. In the present report, we present the results of the BALB/c host immune response in chronically infected survivors after aerosol exposure to 10 separate human clinical strains of B. pseudomallei.…”

“…This underscored the importance of getting a better understanding of different clinical strains of B. pseudomallei with their interaction with the host [25]. In a recent study a number of human clinical isolates of B. pseudomallei with documented low passage number were collected, and their virulence was evaluated in a 21 day median lethal dose (LD 50 ) study in a BALB/c murine model of melioidosis after aerosol exposure [29]. This study presented us with the unique opportunity to examine chronically infected BALB/c mice after the 21 day LD 50 aerosol study to ascertain if there were differences in the murine host response when many different clinical strains of B. pseudomallei were evaluated under similar conditions.…”

Dose‐dependant acute or subacute disease caused byBurkholderia pseudomalleistrain NCTC 13392 in a BALB/c aerosol model of infection

“…Other researchers have also noted a lowering of LD 50 values, in mice, when they compared the LD 50 results from 21‐day and 60‐day duration intraperitoneal infection studies with other strains of B. pseudomallei (Welkos et al ). Recent low‐dose, aerosol challenge studies comparing different clinical isolates of B. pseudomallei in BALB/c mice describe an LD 50 value of 25·1 CFU for K96243 (prototype strain), 0·99 CFU for HBPUB10134a and 0·35 CFU for MSHR5855 (Trevino et al ). A working hypothesis is that the virulence of NCTC 13392 falls somewhere between these strains.…”

“…A property of NCTC 13392 in particular, is that the LD 50 is likely to be inversely proportional to the study length due to its subacute characteristics, at low dose. The bacterial burden in the lungs and spleens of BALB/c mice infected with HBPUB10134a and MSHR5855 (delivered by aerosol with doses 6 CFU and 1·2 CFU respectively) is higher than mice infected with a low dose (8 CFU) of NCTC 13392 at day 10 pc, indicating that the infection caused by these other two strains, at low doses, becames established more quickly (Trevino et al ).…”

“…Prior to evaluation, however, the decision about which mouse strain, the route of infection and which strain of B. pseudomallei to use is challenging as a variety of studies have been reported (Jeddeloh et al 2003;Titball et al 2008;Lever et al 2009;West et al 2010;Conejero et al 2011;Thomas et al 2012;West et al 2012;Lafontaine et al 2013;Massey et al 2014;Welkos et al 2015;Trevino et al 2018),. Some studies show BALB/c mice to be more sensitive to infection with B. pseudomallei and thus help reflect acute human infection, while C57BL6 have been shown to be more resistant and thus mimic chronic infection (Leakey et al 1998;Hoppe et al 1999;Liu et al 2002;Tan et al 2008;Bearss et al 2017;Trevino et al 2018). Conversely, a chronic model of infection in BALB/ c mice has been recently reported which utilizes a strain of B. pseudomallei 1106a, which has low virulence, delivered intraperitoneally (Amemiya et al 2015).…”