The arms race at the heart of diseases: new review summarises what we know about how our cells combat microbial invasion

11th November 2022

The coronavirus pandemic has thrown into sharp relief the gaps in our current knowledge about how our bodies fight back against infections.

A microscopy image of virus particles that are shown emerging from the surface of a cell cultured in the lab.

SARS-CoV-2—also known as 2019-nCoV, the virus that causes COVID-19. Credit: NIAID, CC BY 2.0

A new review by Professor Tom Wileman from the Quadram Institute and University of East Anglia has pulled together what’s known about one critical aspect of this defence response – how cells target invading viruses, bacteria, and other microbes for destruction.

These processes are crucial for removing disease-causing pathogens and preventing them from doing more harm. Understanding the complexities of how our cells target pathogens for destruction can help us support our immune system against pathogens and prepare us for future pandemics.

The review, published in the journal Science Advances was written with colleagues from the Norwich Research Park and the University of Liverpool; it describes our current understanding of where our cells stand in what is an ongoing arms race against microbial invaders, and highlights where ongoing research is filling gaps in our understanding.

The cells in our bodies have external membranes that are capable of engulfing foreign bodies, including microbes, by a process called endocytosis or phagocytosis; this brings microbes inside the cell where they can be destroyed by cellular defences. However, pathogens can hijack this system by using the cell’s membrane to shield themselves from detection and destruction giving them time to launch counter offences.

How cells respond to these early stages of invasion is the focus of this review. This is a critical stage in the infection process as it provides the vital pointers needed to develop ways of preventing infections before they take hold, particularly in cases where no immunity has been built up.

Recent studies have shown that endosomes and phagosomes that have engulfed pathogens are tagged by a key protein called LC3 which identifies them as ‘infected’ and targets them for fusion with defence cells called lysosomes. Lysosomes then use a combination of acid and powerful enzymes to kill the pathogens. Researchers are now investigating the significance of this LC3-associated phagocytosis (LAP) in combating infection.

As an example, Prof. Wileman and colleagues from the Quadram Institute and universities of Liverpool, East Anglia (UEA) and Bristol have developed LAP-deficient mice to help study viral lung infections.  The loss of LAP made these mice highly susceptible to influenza A virus, triggering an inflammatory response known as a ‘cytokine storm’; cytokine storms also occur in humans following influenza or Covid-19 infection leading to life threatening pneumonia. In contrast, in mice that had LAP, viral entry into cells was slowed and virus replication in the lung was reduced. If this LAP system is the same in humans then it is likely to be a first defence against respiratory viruses like influenza and SARS-CoV-2.

As these defence mechanisms are so important, research teams across the world are piecing together the details of how they work; what the triggers are that initiate a response; and how the complexes of proteins required for LAP recruitment to cell membranes are assembled to coordinate these defences. A number of related LAP-like pathways have been uncovered and this review provides a detailed breakdown of our current knowledge about them.

A major frontline battle zone where this knowledge is vitally important is in the gut lining which is exposed to a myriad of potential invaders brought into the body on our food or in water. Salmonella and Listeria bacteria are among the leading causes of foodborne illness worldwide, and most cases start with bacteria entering the small intestine and invading cells lining the gut by endocytosis.

Salmonella and Listeria deploy an arsenal of virulence factors to counter cellular defences so they can live and replicate in cells.  This is one reason why they remain such potent causes of disease, despite major efforts to limit their impact. The review describes the growing evidence that LAP and LAP-like pathways play important roles in combating infection by Salmonella and Listeria and how these pathogens try to inhibit LAP to survive.

The tell-tale signals generated by pathogens that trigger LC3 itself are also being unpicked. As presented in the review, it seems that LC3 responds to an increase in pH in the cell, caused by pathogens damaging the membranes or generating pores.

The next steps will be to fully understand these signals and the chain of events they bring about to remove pathogens. It will also be important to identify the factors pathogens deploy to slow these defences, another step in the ongoing arms race between pathogen and host.

Reference: Control of infection by LC3-associated phagocytosis, CASM, and detection of raised vacuolar pH by the V-ATPase-ATG16L1 axis, Yingxue Wang, Maria Ramos, Matthew Jefferson, Weijiao Zhang, Naiara Beraza, Simon Carding, Penny Powell, James P. Stewart, Ulrike Mayer, Thomas Wileman, Science Advances DOI: 10.1126/sciadv.abn3298

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Targeting food safety

Food Safety

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Tom Wileman

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