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Randall Basaraba

Associate Professor

Office: 314 Pathology
Office Phone: 970-491-3313
Email: randall.basaraba@colostate.edu

Research Interests

The focus of our laboratory is the pathogenesis of mycobacterial infections in laboratory animals as models of tuberculosis in humans and cattle. Tuberculosis in humans is caused by the rod shaped acid fast bacterium Mycobacterium tuberculosis and less frequently Mycobacterium bovis. In cattle and other ruminant species, tuberculosis is cause almost exclusively by M. bovis. Mycobacteria have developed mechanisms to evade and survive the host inflammatory and immune responses. One mechanism is by infecting and thriving within macrophages, cells that are among the most important for controlling the infection. If macrophages are unable to kill the bacilli, the host responds by mounting an aggressive inflammatory response in an attempt to contain the infection and prevent further spread of disease. The lesion that results from chronic mycobacterial infections is granulomatous or pyogranulomatous inflammation consisting of a mixture of mononuclear and polymorphonuclear leukocytes. One of the consequences of a progressive mycobacterial infection is that granulomatous inflammatory lesions expand in size, resulting in central lesion necrosis.

Figure 1. A granulomatous inflammatory lesion from a Mycobacterium tuberculosis infected guinea pig.

The Pathogenesis of Caseous Necrosis

Lesion necrosis is important because it results in irreversible damage that adversely affects tissue structure and function. Caseous necrosis is a hallmark feature of tuberculous granulomas in human infections and a variety of naturally occurring and experimental animal infection models. One of the only ways in which lesions with caseous necrosis can heal is by deposition of fibrous connective tissue and a complex mineralized matrix called dystrophic calcification. These processes represent tissue scarring that can persist for many years or even the life of the individual. The pathogenesis of caseous necrosis is poorly understood and is a major focus of our research. We are currently testing the hypothesis that as the inflammatory lesions expand in size, the tissue blood supply is disrupted, leaving both parenchymal and inflammatory cells deprived of oxygen. This type of cell death is referred to as ischemic necrosis. We are testing this hypothesis in the Guinea pig model of tuberculosis because they develop granulomas with caseous necrosis and dystrophic calcification similar to what is seen in humans and cattle (Figure 1). Understanding how the lesion develops may lead to novel strategies to prevent the adverse tissue damage associated with mycobacterial infections.

Figure 2. A granulomatous inflammatory lesion from a Mycobacterium tuberculosis infected Guinea pig. The area of central necrosis contains numerous extra-cellular bacilli (red) enmeshed in a matrix composed of macromolecules from necrotic host cells. The blue staining material is DNA and the green staining protein is B-actin which makes up the host cytoskeleton of viable inflammatory cells. Immunofluorescence.

Mechanisms of Extracellular Survival

The other major focus of our research is investigating what affect lesion necrosis has on the ability of M. tuberculosis and other mycobacteria to survive in an extra-cellular environment in the presence of necrotic host cells. When infected cells die, the bacilli are released and become entrapped in a complex matrix composed of host cell derived macromolecules like DNA (Figure 2). Bacteria enmeshed within these macromolecules are further isolated from the host defense mechanisms and may be difficult to kill with antimicrobial drugs. Since drugs are carried to infected tissues through the circulation, lesions with a poor blood supply may not achieve sufficient drug levels to kill bacilli. Another factor that may influence bacterial drug susceptibility is the changed bacterial physiology when bacilli are attached to an extra-cellular matrix. Attachment to a complex matrix is the first step in the formation of microbial communities often referred to as biofilms. We are testing the hypothesis that mycobacteria utilize host macromolecules derived from necrotic cells to initiate biofilm formation in vitro and in vivo (Figure 2 and 3). Understanding how bacteria tolerate drug therapy may lead to innovative approaches to cure these refractory infections.

Figure 3. The vaccine strain of Mycobacterium bovis (BCG), preferentially binds to macromolecules derived from bovine neutrophils in vitro. The blue strands are neutrophil extra-cellular traps (NETs) composed of DNA that entraps bacilli (red) that grow as attached microcolonies. Immunofluorescence.

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