Infectious Disease Research

Expanding populations – and the ease with which humans now travel globally – have given deadly and resistant pathogens new opportunities to emerge and thrive. Infectious diseases that were once geographically confined now spread from country to country, continent to content more rapidly than ever before.

Developing effective vaccines and therapies for these diseases is crucial to protect the safety of people around the world. Currently, there are no proven vaccines or medications to address the high-consequence and antibiotic-resistant pathogens that have caused illness and death on multiple continents over recent decades, such as Ebola, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East Respiratory Syndrome coronavirus (MERS-CoV), multi-drug-resistant tuberculosis and Methicillin-resistant Staphylococcus aureus (MRSA). Infectious Disease Research

A key challenge, both to understanding the pathogenesis and transmission potential of these viruses and to evaluating possible therapeutic and vaccine approaches, is the current absence of cell-culture systems that can be infected by them. The majority of research models used today let researchers explore subjects’ susceptibility to infection or the virus’ replication patterns, but they do not provide an adequate representation of what the diseases actually do in humans. Finding a mammalian species with the ability to be infected by each of these pathogens is essential to moving forward in the vaccine and drug discovery process.

Why not simply use a human lung cell line? A cursory search of the American Tissue Culture Collection (ATTC) reveals human lung cell lines that are derived only from fetuses or from lung cancers. Employing these cell lines in drug-screening research can introduce experimental artifacts due to their embryonic and cancerous origins.

A primary focus of our team in SRI International’s Center for Infectious Disease Research is developing unique and practical research models that are more representative of infectious disease in humans. As an example, we recently identified a model that we believe may expedite the development of vaccines and treatments for MERS-CoV, a deadly disease that was first identified in humans just three years ago.

MERS-CoV infections are characterized by acute respiratory distress and can be fatal. Until recently, no cell lines existed that could be invaded by this virus, making the initial step of screening compounds for activity against MERS extremely challenging.

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Soon after the disease emerged in 2012, our lab began looking at cells from various species to determine if they could provide a good model of MERS-CoV infection and replication. Our research focused specifically on determining whether or not a certain host-cell protein, known as dipeptidyl peptidase 4 (DPP4), was present on the surface of these cells. We know from previous research completed by V. Raj and colleagues at Erasmus Medical School that the coronavirus responsible for MERS uses (and requires) this receptor protein to enter human cells. Using this knowledge, we examined cells for the presence of DPP4 on the surface that would allow binding and entry of MERS-CoV.

At a recent infectious disease conference, our lab presented data showing for the first time that a cell line derived from the lung cells of American mink can be infected by MERS, and that these cells express inflammatory mediators also detected in the lungs of MERS patients and laboratory-infected human cells. Infection of mink lung cells leads to the death of these cells, recapitulating the effect of MERS in human lung tissue.

Further characterization of the mink cell-line shows that DPP4 in mink is expressed in at least three different isoforms. Each one, when cloned and transfected into a control cell line, allows MERS infection. Alignment of the mink amino-acid sequence with the human sequence further suggests that similarities exist between human and mink DPP4 that allows cells from both species to be infected with MERS.

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