The body's response to infection by SARS-CoV-2 (the virus that causes COVID-19) varies across different cell types, according to a new study.
US researchers used organoids grown from human induced pluripotent stem cells to model how the virus affects cells of different organ systems. Although primarily a respiratory disease, COVID-19 can affect other organs in ways that are not fully understood, resulting in symptoms as diverse as arrhythmia, long-term fatigue and inability to think clearly.
'We're finding that SARS-CoV-2 doesn't infect the entire body in the same way. In different cell types, the virus triggers the expression of different genes, and we see different outcomes,' said research leader Professor Tariq Rana from the University of California San Diego School of Medicine.
Organoids are used as models to replicate some of the complexity of whole organs, although they lack immune cells and blood vessels. In this study they were used to model lung and brain tissues and, like their respective organs, they show ACE2 and TMPRSS2 receptors on the cell surface which are known binding targets for the virus' 'spike proteins'.
Expression of ACE2 and TMPRSS2 on the surface of the lung and brain cells was explored by attaching a fluorescent marker to a non-infectious variant of the virus and exposing the tissues to it. The marker allowed the amount of binding of the pseudovirus spike proteins to be quantified which helped indicate the level of infectivity of the virus in each tissue, showing lung organoids were much more susceptible.
The lung organoids had a ten-fold higher expression of ACE2 and TMPRSS2 proteins than the cells from the brain. Four different types of cells from the brain were tested, including cerebral organoids, and all showed lower levels of binding.
Differences in cell responses were also seen between the two types of tissue. The immune response in lung organoids involved expression of molecules known to mobilise immune cells: molecules such as interferons and cytokines. In contrast, brain organoids increased expression of molecules known to stimulate the innate immune response and support recognitions of pathogens. These molecules also support programmed cell death.
Professor Rana explained this could be significant as his team previously saw a similar reaction in brain cells infected with Zika virus – a virus known to stunt brain development in newborn babies.
The team also verified their findings by replicating the study using live SARS-CoV-2 virus in a biosafety laboratory specifically designed to handle high-risk infectious microbes.
The team are now supporting drug-discovery efforts by developing SARS-CoV-2 inhibitors and testing them on organoids derived from stem cells from donors of a variety of ethnic backgrounds.
The research was published in Stem Cell Reports.