Transmission of pathogens from vertebrate animals to humans has caused major epidemics in the past and continues to pose threats to the human population. To cope with viral infections, vertebrate species have evolved response strategies for resistance (including adaptive and innate immunity) and tolerance (pathogen or defense-induced damage is reduced) to infection.
Species that tolerate infections can carry a high burden of infectious agents and, therefore, may be important reservoirs for transmission to other species. For instance, bats tolerate viral infections that have spread to humans causing diseases such as Ebola, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS).
Pangolins have been identified as a potential source of SARS-CoV-2, the cause of the COVID-19 respiratory disease. The immune defense of the toothless insectivores has not been previously characterized. It is known that the receptor of SARS-CoV-2, angiotensin I-converting enzyme 2 (ACE2), is conserved in pangolins, and coronaviruses isolated from pangolins have a receptor-binding domain (RBD) in their spike proteins that is very similar to that of SARS-CoV-2.
Understanding how pangolins tolerate infection with coronaviruses and their evolutionary advantage may point to possible treatment options for coronavirus infection in humans.
To explore the antiviral defenses of pangolins to RNA viral infections, researchers analyzed genome sequences of several pangolin species for the presence of sensors of intracellular RNA such as melanoma differentiation-associated protein 5 (MDA5) and Z-DNA-binding protein 1 (ZBP1). MDA5 is encoded by the interferon-induced helicase-1 (IFIH1) gene and functions as a pattern recognition receptor capable of detecting viruses and activating expression of interferons. Zinc metalloprotease-1 (ZMP1) recognizes DNA in the cytoplasm as an antiviral mechanism and leads to the production of antiviral cytokines such as interferon beta.
In silico translation of pangolin MDA5 and ZBP1 pseudogenes -- nonfunctional segments that resemble functional genes -- reveals that while the sequences for the genes exist, no functional signaling proteins are produced. Based on phylogenic tree mapping, the researchers suggested that the loss of both IFIH1 and ZBP1 genes occurred in pangolins soon after divergence from the lineage leading to Carnivora (which contains cats, dogs, and bears).
Other genes encoding intracellular RNA sensor retinoic acid-inducible gene I (RIG-I; pattern recognition receptors responsible for type 1-interferon responses) and toll-like receptors (TLR-3, -7, -8; control sensing of RNA in endosomes) do not contain disruptive mutations and appear to be intact.
The loss of the ZBP1 and IFIH1 genes may have provided an evolutionary advantage to pangolins by increasing their tolerance to infections by certain RNA viruses, including coronaviruses, according to the researchers.
Coronavirus can cause an overreactive inflammatory immune response (cytokine storm) from the overproduction of signaling proteins in response to the virus. Pharmaceutical suppression of gene signaling -- perhaps of ZBP1 and IFIH1 -- could be a possible treatment option.
"The main challenge is to reduce the response to the pathogen while maintaining sufficient control of the virus," said co-author Leopold Eckhart, PhD, of the Medical University of Vienna in Austria, in a statement. The immune system can be moderated "by reducing the intensity or by changing the timing of the defense reaction."
The researchers did not study the impact of genomic differences on antiviral responses, but they believe that the lack of the two signaling genes may be associated with the ability of pangolins to survive coronaviruses.
"Our work shows that pangolins have survived through millions of years of evolution without a type of antiviral defense that is used by all other mammals," explained Eckhart. "Further studies of pangolins will uncover how they manage to survive viral infections, and this might help to devise new treatment strategies for people with viral infections."
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