Smith, Leanne May
(2015).
Investigating phagosome dynamics of microbial pathogens.
University of Birmingham.
Ph.D.
Abstract
Many microbial pathogens are able to evade killing by phagocytes of the innate immune system. This thesis focuses on two pathogens: the fungal pathogen \(Cryptococcus\) \(neoformans\) and the bacterial pathogen \(Streptococcus\) \(agalactiae\). \(C\). \(neoformans\) causes severe cryptococcal meningitis in mostly immunocompromised hosts, such as those with HIV infection. In contrast, \(S\). \(agalactiae\) is the leading cause of neonatal sepsis and meningitis. The interaction between macrophages and these pathogens is likely to be critical in determining dissemination and outcome of disease in both instances.
A collection of \(S\). \(agalactiae\) clinical isolates, ranging in origin from colonisation cases to severe infection cases, were tested for their ability to persist with a macrophage cell line. Surprisingly, persistence within macrophages was a characteristic shared by all of the isolates tested. Furthermore, by investigating the \(Streptococcus\)-containing phagosome, it was revealed that streptococci are able to manipulate the acidification of macrophage phagosomes.
Similarly, the maturation of phagosomes containing the fungal pathogen \(C\). \(neoformans\) was explored. Cryptococci are shown to be able to manipulate the phagosome they reside within. This is driven by modified acquisition of Rab GTPases to the phagosome, as well as altered acidification and cathepsin activity within \(Cryptococcus\)-containing phagosomes.
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