A rhesus macaque (Macaca mulatta) model of aerosol-exposure brucellosis (Brucella suis): pathology and diagnostic implications

Abstract

The US Centers for Disease Control and Prevention lists Brucella as a potential bioterrorism threat requiring enhanced diagnostic capacity and surveillance (http://emergency.cdc.gov/bioterrorism/). Successful treatment and management of patients after exposure to biological threat agents depends on accurate and timely diagnosis, but many biothreat agents present with similar, vague clinical signs – commonly referred to as ‘flu-like illness’. Diagnosis of brucellosis is notoriously challenging, especially early in infection, and definitive diagnosis may require invasive methods, e.g. bone marrow biopsy. We studied the pathogenesis of Brucella suis aerosol infection in rhesus macaques in an effort to guide the diagnostic algorithm in case of possible intentional exposure of humans. Rhesus proved to be an excellent model for human brucellosis; the data showed that PCR DNA amplification testing of non-invasive diagnostic samples has the potential to definitively detect a point-source outbreak immediately and for several days after exposure.

Pathophysiology of the Rhesus Macaque Model for Inhalational Brucellosis

“…An adverse effect of brucellosis on the liver in the current study was supported by positive liver biopsies, liver tissue burdens, and microscopic observations of hepatocellular necrosis. In addition to a limited change in clinical pathology parameters, a limited effect on clinical hematology parameters was observed in the B. suis aerosol-challenged acutely infected RMs (24). This is consistent with the results from the current study.…”

“…The changes observed in clinical pathology and hematology parameters in this study were consistent with human brucellosis, in which the majority of clinical pathology indicators are indistinct (24). In addition, a recent study observed limited changes in clinical pathology parameters in RMs that were monitored for 7 days after challenge (acute infection) with a high dose of 5.60Eϩ08 CFU B. suis (24).…”

“…In this study, we observed that RMs had increases in liver enzymes AST, CRP, ALT, ALP, and LDH during the 8-week postchallenge period. Other clinical chemistry parameters (i.e., creatinine, BUN, and glucose) in infected RMs were not different from baseline, which is similar to human brucellosis (24). Figure 2 illustrates the trends for some of the clinical pathology parameters during the 8-week postchallenge period for challenged and unchallenged animals that were not euthanized until day 56 (groups 9 and 10) and could therefore be used to show the kinetics of these parameters.…”

“…In addition, a recent study observed limited changes in clinical pathology parameters in RMs that were monitored for 7 days after challenge (acute infection) with a high dose of 5.60Eϩ08 CFU B. suis (24). The only clinical pathology parameters that were affected in the current chronic infection study were liver enzymes (LDH, ALT, AST, and ALP), which is consistent with the mild increase in liver enzymes (LDH and ALP) that has been observed in human brucellosis patients (3).…”

“…While there are only minimal data from NHP studies, one study showed that rhesus macaques (RMs) were susceptible to infection by aerosolized B. melitensis as demonstrated by tissue burden and histopathology (18). A second study monitored the tissue burden and histopathology of RMs for 7 days after aerosol challenge with a high dose of Brucella suis (24). A well-understood pathophysiological mechanism of toxicity and a sufficiently well-characterized animal model for predicting the response in humans are two key components of the Animal Rule (21 CFR 314.600 for drugs and 21 CFR 601.90 for biological products).…”