Virus World

This case series describes rare putative X-chromosomal loss-of-function variants associated with impaired peripheral mononuclear blood cell interferon signaling in 4 young male patients hospitalized with severe coronavirus disease 2019 (COVID-19) in the Netherlands. Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.

Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments. Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.

The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod. In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

Published in JAMA (July 24, 2020):

https://doi.org/10.1001/jama.2020.13719

The Epstein-Barr virus (EBV) is very widespread. More than 90 percent of the world's population is infected, with varying consequences. Although the infection does not usually affect people, in some, it can cause glandular fever or various types of cancer. Researchers at the German Cancer Research Center (DKFZ) have now discovered why different virus strains cause very divergent courses of disease.

 More than 90 percent of all people become infected with the Epstein-Barr virus (EBV) during their lifetime. The infection usually remains undetected. However, the virus can also cause diseases—with regional differences: Glandular fever (infectious mononucleosis) primarily occurs in Europe and North America, and normally affects adolescents or young adults. In equatorial Africa, Burkitt lymphoma is associated with EBV infection. And in Taiwan, southern China and Southeast Asia, the virus often causes nasopharyngeal carcinomas, cancers of the nose and throat area. This is one of the most common types of cancer in young adults in these countries.

"Nasopharyngeal carcinomas are sometimes seen here too, but really very rarely," commented Henri-Jacques Delecluse from DKFZ. So how does EBV cause completely different diseases in different parts of the world? "One possible explanation is that different types of virus are responsible," Delecluse explained. "And we have now found evidence of precisely that." The DKFZ researchers are publishing their results in the journal Nature Microbiology.

In the laboratory, Delecluse and his team studied a virus strain that had previously been isolated from a nasopharyngeal carcinoma. M81, as this particular type of virus is called, has certain peculiarities. The researchers had previously discovered that M81 infects not only the immune system's B cells, but also epithelial cells of the nasal mucous membrane very efficiently. In contrast, virus strains that cause glandular fever in Europe almost only infect B cells. And although the virus strains that are common there cause the infected B cells to multiply in a Petri dish, they do not produce any new virus particles, unlike M81. To find out how this variant affects the behavior of the virus, the DKFZ researchers used molecular biology tools to extract EBER2 from the M81 genome. "The virus was, indeed, no longer able to multiply in the infected cells," Delecluse noted. Even when an EBER2 element from a virus strain that is widespread in Europe was inserted into the M81 virus, it was no longer able to produce virus particles.

"We have therefore finally found evidence that different types of virus can be responsible for different diseases," said Delecluse, emphasizing the significance of his results. "This finding is a strong argument for pressing on with vaccine research in order to develop protection against the most dangerous strains of EBV in future," he concluded. The vaccination against human papillomavirus (HPV), which can cause cervical cancer, already uses a similar principle.

Findings published in September 9, 2019 in Nature Microbiology:

https://doi.org/10.1038/s41564-019-0546-y