Kha Phan - Cell death, dead cell clearance and infection
Apoptosis, a type of a programmed cell death, is a key host defence that destroys pathogenic niches in infected cells, kills infectious agents and initiates adaptive immunity. Dying cells have an active role in alerting the immune system, by attracting phagocytes (e.g., dendritic cells, macrophages). Furthermore, dying cells often break into ‘bite-sized’ membrane-bound fragments called ‘apoptotic bodies’ (ApoBDs) to enhance corpse engulfment and removal by phagocytes (a process known as ‘efferocytosis’). In turn, the phagocytes process the ApoBD contents and activate their own signalling programs, specific to the type of molecular messages that they have recognised.
The Phan group aims to advance current understanding of the dynamic host-pathogen interaction along apoptosis–efferocytosis axis and to develop novel therapeutics for respiratory infections, the leading pathogenic causes of global morbidity and mortality.
Research areas
Efferocytosis-mediated viral entry and inflammation
Severe SARS-CoV-2 infection is typified by an exacerbated pro-inflammatory 'cytokine storm', which develops after peak viral titre. Macrophages, rapid cytokine producers upon pathogen infection, are a major driver of COVID-19-associated hyperinflammation. Hitherto, it remains unclear how SARS-CoV-2 gains entry into macrophages, which lack canonical receptor required for viral entry, and triggers hyperinflammation. We recently discovered that SARS-CoV2-induced ApoBDs mediate a novel viral uptake pathway, by primary human macrophages and other phagocytes. Of great clinical significance, SARS-CoV-2-ApoBD-engulfing macrophages, secreted markedly high levels of cytokines. We thus aim to uncover the novel mechanism of infection-derived ApoBDs in facilitating viral uptake and driving inflammation, and develosp novel ApoBD-targeting therapeutics to tackle other apoptosis-inducing newly emerging virals threats.
Mtb and many intracellular bacteria have evolved to prevent host apoptosis to escape host immunity and enhance their growth in infected cells. Hence, therapeutic induction of infected cell apoptosis and promotion of ApoBD formation may reinstate host anti-infective responses through ApoBD-mediated T cell activation. We will conduct world-first groundwork for the therapeutic enhancement of ApoBD formation to promote host-mediated clearance of Mtb infection by combining MAIT cells (for specific apoptosis induction of infected cells) and pharmacologically inhibiting ApoBD formation.
Collaborators:
A/Prof. Anna Coussens (WEHI)
A/Prof. Edwin Leeansyah (Tsinghua Shenzhen International Graduate School, China)
Novel regulators of ApoBD formation and efferocytosis
Apoptotic cell death underpins many critical physiological and pathological processes, not only infection but also cellular homeostasis, development, ageing and immunity. The communication between dying cells and healthy cells can be relayed by ApoBDs. In addition, the fragmentation of apoptotic cells into “bite-sized” ApoBDs mediate the rapid and efficient debris removal via efferocytosis. However, the molecular basis of ApoBD formation and efferocytosis remains poorly understood. We seek to identify novel regulators of ApoBD formation using proteomics and CRISPR/Cas9 screening.
As ApoBD formation and efferocytosis play important roles in many critical cellular processes and diseases, we aim to perform multiple drug library screening as well as rationalised drug designs to identify ApoBD-targeting small molecules as novel therapeutics.
