Abstract
When individuals become infected with any virus, the first question often is, how sick will they get? The coronavirus disease 2019 (COVID-19) pandemic highlighted this notion for all of us. The greatest risk factor for hospitalization and death was quickly realized to be age, but as always, there were exceptions. There were cases of young vaccinated individuals getting very sick with COVID-19, and at the same time, most of us know of an elderly individual who experienced only mild symptoms, even before vaccines were available.
Now that the urgency of the pandemic seems to have subsided, we finally have time to truly understand this virus and the disease it causes. One main focus going forward will be to figure out what else predicts disease severity, who is most at risk for severe disease, as well as which factors contribute to the development of long COVID-19.
Many virus infections present with similar inflammatory profiles, and for many of these infections, we do not yet know what predicts disease severity. In this issue, Jose et al. have investigated the expression of indoleamine 2,3-dioxygenase (IDO) 1 pathway genes in severe dengue patients. Using a principal component analysis, the authors examined the relationships between gene expression profiles and disease severity, as well as laboratory markers of clinical severity. Based on their findings, they concluded that profiling the baseline expression patterns of IDO pathway genes can aid in the identification of dengue patients most at risk for severe disease.
Also on the topic of innate immunity, Zhang et al. examined Toll-like receptor 3 (TLR3) gene single nucleotide polymorphisms (SNPs) in 370 Kaposi's sarcoma-associated herpesvirus (KSHV; HHV8)-infected patients to look for effects on interferon (IFN)-γ levels. The authors identified two TLR3 SNPs that showed protective effects against KSHV infection, and from this they concluded that genetic variants in TLR3 reduce the risk of KSHV infection and affect KSHV reactivation among HIV-infected individuals, especially in the Uyghur population.
As already mentioned, the ability to predict disease severity in COVID-19 would be extremely valuable. In an article by Gabr et al., T lymphocyte subsets and NK cells were analyzed in moderate and severe cases of COVID-19. The team found that the relative and absolute counts of some immature NK lymphocytes were higher in severe cases with worse outcome and death. They also found a positive correlation between immature NK cells and interleukin (IL)-6 levels. Based on these findings, they proposed that some immature NK subsets contribute to widespread inflammatory responses that complicate severe COVID-19.
Still on the topic of disease severity in COVID-19, Galán-Huerta et al. went searching for host polymorphisms related to the severity of COVID-19 among 117 hospitalized patients in Mexico with no known comorbidities. The study found that carriage of IL-1 B*-31 *C was an independent risk factor for ICU admission, and that the presence of IL-RN*2 was a protective factor. Given the spectrum of disease severity observed in COVID-19 cases, even within older age groups, we can only assume that other genetic factors must also be involved.
Given the high morbidity and mortality rates associated with the Middle East respiratory syndrome coronavirus (MERS-CoV) infection, there is much interest in predictors of disease severity for this virus. Here, Alhetheel et al. assess symptomatic and asymptomatic MERS-CoV-infected individuals, alongside 52 healthy controls, with respect to a panel of inflammatory cytokines. It was found that all cytokines measured had higher levels in symptomatic patients, but, in particular, IL-7 was found to have a higher risk ratio for mortality. This finding indicated that IL-7 might serve as a marker for disease severity in MERS-CoV infection, as well as for other viruses.
The final article in this issue deals not directly with predicting disease progression, but instead takes a look into what happens when a chronic infection is cured and whether or not the immune system gets restored. Hepatitis C virus (HCV) infection used to result in 70–85% of cases progressing to chronic lifelong infection leading to destruction of the liver over decades of time. Now, with the development of effective and curative direct-acting antivirals (DAAs) targeting HCV, we have the opportunity to study immune restoration after, in many cases, decades of immune dysfunction.
In line with this theme, accumulation of myeloid-derived suppressor cells (MDSCs) is one of the known immune alterations observed in chronic HCV infection. Abdulsamad et al. have investigated MDSCs in treated versus untreated HCV-infected individuals in Egypt and found that DAA-treated patients had lower percentages of MDSCs than untreated patients. The authors interpreted this finding to indicate partial retrieval of immune regulatory function after DAA therapy.
In closing, we wish to thank all authors for their outstanding research contributions, all reviewers for volunteering their time to help ensure the quality of work published in our journal, and of course to all study subjects for providing crucial samples that help us understand the immune responses against these viruses.