Date of Degree

9-2017

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor(s)

Jayne Raper

Committee Members

Michael Steiper

Weigang Qiu

Nina Papvasiliou

Rachael Zufferey

Subject Categories

Immunology of Infectious Disease | Parasitology | Pathogenic Microbiology

Keywords

Leishmania, TLF, APOL1, HPR, Trypanosome, Neutrophils

Abstract

Trypanosome Lytic Factor (TLF) is an innate immunity complex that was originally discovered to protect against African Trypanosomes. The major components of TLF are Apolipoprotein A1 (APOA1), Apolipoprotein L1 (APOL1) and HPR (Haptoglobin Related Protein), where APOL1 is necessary and sufficient for trypanolysis. Recently we have shown that TLF ameliorates infections by cutaneous Leishmania species. Here we investigated the effect of different primate and human TLF against different Leishmania sp. Our result shows that TLF kills metacyclic promastigotes of cutaneous Leishmania sp. within immune cells such as neutrophils and macrophages by two different mechanism. Using transiently transfected and germline transgenic mice, we show that baboon as well as human TLF is effective at protecting against cutaneous Leishmania sp. that depends on TLF as well as infectivity dose. We found neutrophils are important for this TLF mediated immunity where TLF activity initiates in acidic phagosome of neutrophils leading to lysis of the metacyclics when they are released in the extracellular milieu. We also investigated the effect of TLF against parasite in macrophages. Using our in vitro assay that ostensibly mimics macrophage phagosome and parasitophorous vacuole, we show that TLF mediated lysis of metacyclics also occur when there is gradual acidification in maturing phagosome. However, proliferating parasites such as metacyclics of visceral strains and amastigotes of cutaneous strains are resistant to TLF activity. This resistance possibly depends on surface glycoproteins as glycosylation deficient mutants are resistant to TLF. In conclusion, our results show that TLF is an important immunity complex that synergize with immune cells like neutrophils and macrophages to kill metacyclics of cutaneous Leishmania sp.

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