International Collaboration Identifies Biological Markers of COVID-19 Severity

NIAID CEIRS | Research Publication Commentary

Arunachalam PS et al. (2020) Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans. Science.

Since the beginning of the COVID-19 pandemic, medical professionals have noted more severe infections and a higher mortality rate in older individuals and those with chronic medical conditions. Unfortunately, the physiologic reason for this has not yet been established. To better understand the immunologic features of COVID-19 infections and the risk factors in older or comorbid patients, a team of researchers from both the US and Hong Kong recently published a study in Science investigating differences in immune responses between mild and severe COVID-19 infections. The researchers, including members of the St. Jude Center of Excellence for Influenza Research and Surveillance (SJCEIRS), investigated clinical history and immune responses from patients at the Princess Margaret Hospital at Hong Kong University and the Hope Clinic at Emory University.

Artist’s interpretation of SARS-CoV-2 in the bloodstream.

The innate and adaptive immune systems work together to respond to various threats introduced into the body. Broadly, the innate immune system responds to pathogens non-specifically and can act very quickly, often within hours. The adaptive immune system develops “memory” specific to individual pathogens. This process can take several weeks but allows the body to respond quickly to re-infection with a similar pathogen. This study assessed several of the components of both the innate and early adaptive immune responses, including dendritic cells and cytokines. Dendritic cells are an immune system component that works to identify antigens in the body and destroy infected cells. As part of this process they release various cytokines, which are signaling molecules that increase or decrease inflammation in response to infection. Cytokines can be released from different cells of the immune system circulating in the blood or from tissues at a site of infection. One of the cytokines studied in this study is interferon, which can inhibit viral replication.

The patients in this study were separated by type and severity of infection. In patients with mild infection, the authors found a decreased production (compared to healthy patients) of interferon from dendritic cells, which are part of the innate immune response. Expression of interferon can directly inhibit viral replication but can also promote antiviral activity in neighboring cells. In addition, expression of other cytokines from dendritic cells was markedly suppressed, meaning these cells were not as responsive to pathogens as they would be normally. Previous studies have regularly identified lymphopenia, or decreased number of innate immune system cells, in patients with COVID-19. Because all COVID-19 patients in this study had both lymphopenia and decreased interferon response, it suggests that infection can lead to a generalized suppression of innate immune function, regardless of severity. Effects on the adaptive immune system are uncertain.

Compared to mild infections, previous studies found that severe COVID-19 infections were associated with an inflammatory state. This finding was confirmed by the authors in this study, but interestingly, they found again that expression of pro-inflammatory cytokines from dendritic cells were suppressed. This profile is similar to patients with mild infections and points to other body tissues as the source these pro-inflammatory cytokines. As COVID-19 initially infects the respiratory tract, lung tissue is the mostly likely source. This is important because it suggests the lung tissue experiences more damage in patients with severe disease, though it is not specified if that is a direct viral effect. The authors then investigated whether other immune markers were correlated with clinical disease severity. One cytokine called TNFSF14 was found to be specific to COVID-19 patients and its expression also correlated with mild or severe disease. Patients with high levels of cytokines also had higher levels of bacterial components in their blood, which suggests a secondary bacterial infection. Clinical data indicate that bacterial infections in these cases are most often pneumonia, which supports a lung tissue origin of the high levels of cytokine expression.

The results of this study identified immune markers that may help clinicians assess a patient’s risk for developing severe disease earlier in the course of infection. Furthermore, the deficiencies in interferon production represent a possible target for therapeutic intervention, though additional research is needed. Recognizing specific cytokines like TNFSF14 is a potential diagnostic tool that may direct clinicians to identify and treat bacterial co-infections earlier. Understanding effects on the innate immune system are critical when combating a novel disease like COVID-19, as the adaptive immune system is unprepared to respond.