Coronavirus and Complement Activation
May 21st 2020
In the last couple of decades, there have been three major epidemics where animal viruses have infected humans. The most recent outbreak is caused by the SARS-CoV-2 virus, a.k.a. 2019-nCoV, which can result in corona virus disease 19 (COVID-19). Before this virus, there were outbreaks of SARS-CoV and MERS-CoV, which cause Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), respectively.
Corona viruses have large single-stranded RNA genomes. They have envelopes that contain the spiked proteins that give them their characteristic crown-like appearance and from which their name is derived. There are around 30 different corona viruses known to infect animals. In humans, the symptoms of the infections range from mild to severe and typically include fever, cough, headache and upper and sometimes lower respiratory tract infection.
There are two major ways our immune system protects us from corona viruses: through innate and adaptive immune responses. Innate responses are the body’s first line of defense and involves several steps including:
- Recruitment of immune cells to the site of the infection by the release of cytokines
- Activation of the complement system
- Identification and clearing of foreign material by specialized white blood-cells
- Activation of the adaptive immune system
Adaptive immune responses create immunological memory and are pathogen specific. These responses are carried out by two major lymphocytes, B and T cells, that drive antibody and cell-mediated responses, respectively. In response to SARS-CoV, CD4+ T cells and CD8+ T cells appear to be the main actors. CD4+ T cells activate T-dependent B cells that produce antibodies against the virus and CD8+ T cells act by killing virus-infected cells through cytotoxic mechanisms. In addition, T helper cells produce cytokines that promote inflammation by recruiting other immune cells that release cytokines and chemokines.
The immune system has to strike a delicate balance between fighting the infection and not overwhelm the body through inflammation and immune-mediated injury.
In a paper examining the role of the complement system in a mouse model of SARS-CoV, Gralinski and colleagues found that virus-infected complement-deficient mice had significantly less weight-loss and respiratory dysfunction compared to wildtype mice. In addition, they found that there was significantly fewer neutrophils and inflammatory monocytes, as well as lower cytokine and chemokine levels, in the lungs of the complement-deficient mice, which could indicate that SARS-CoV-mediated disease is largely immune-driven.
Since the complement system appears to be at least in part contributing to corona virus pathogenesis, drugs targeting components of the complement system could provide effective future therapeutics. In fact, there is currently an ongoing clinical trial where COVID-19 subjects are receiving the complement inhibitor Eculizumab with the hope of reducing the mortality of the disease.
The complement system consists of around thirty proteins that form three distinct pathways: the classical, alternative and lectin pathways. These pathways can be activated in a number of different ways resulting in processing of complement proteins to form cleavage products that are involved in complement activation. Some of the better-known components of the complement system are C3, C4 and C5. Inhibitors against these components could potentially work as biotherapeutic drugs. However, in order to find potential drug candidates targeting complement components, it is important to study how the complement system contributes to disease, which pathways and individual markers that are good drug targets.
What we offer?
Functional and biomarker assays that can be used to explore every angle of complement system-involvement. Our kits are ideal for independent studies of all three pathways of the complement system as well as measure individual components using our biomarker assays. In addition, they have already been used in several clinical trials. Based on the well-established and robust ELISA technology, our products can be used in standard setups as well as automated setups. Ready-to-use reagents contribute to the ease-of-use of the assays.