Layperson Version
Attack on Humanity
Most microorganisms are based on a DNA genome. Some viruses, including the coronavirus, have RNA-based genomes instead. In general, viral RNA genomes are much more mutation-prone than those based on DNA. This distinction is important because RNA-based viral mutations have a greater potential for increased virulence and greater transmissibility. Such are the concerns with the variants developing in the SARS-CoV-2 virus. Different variants are evolving from “mutations” of the viral genome. Studies have shown that some variants spread more quickly than others demonstrating mutation in the virus’s spike protein (more on this below), representing a potential risk of worsening a pandemic.
Viruses are not living cells or organisms. They require a living host to exploit or infect (enter) so they can replicate to complete their life cycle (Figure 7.1). The invading virus uses its DNA or RNA to replicate in the host cell. Coronaviruses (CoV) are a family of RNA viruses that typically cause mild respiratory disease in humans. They include
SARS-CoV-1, thought to be driven by the spillover of bat-adapted CoVs into an intermediate host (more below). The novel coronavirus (SARS- CoV-2) is a single positive-strand RNA virus. These viruses are poorly adapted to the human host and if transmitted to humans, they are generally associated with more severe clinical presentations.
Coronavirus disease leads to fast activation of innate immune cells, especially in patients developing severe disease. Innate immune activation, levels of many proinflammatory cytokines, as well as higher levels of other proinflammatory chemicals leave virtually all organ systems vulnerable to adverse effects from the novel coronavirus. The causes and life cycle of SARS-CoV-2 includes a complex of RNA genomic transfers and regenerations to produce the proliferation of the virus. The virus’ activity inside and outside the host cell are illustrated in Fig. 7.1.
The severity and the clinical picture of the immune response in many patients could even be related to the activation of an exaggerated immune mechanism. The levels of some cytokines are increased often producing a “cytokine storm” or hyperinflammatory state. This chronic inflammatory (CI) clinical response leaves virtually all organ systems vulnerable to adverse effects from the virus. The hypothesis that SARS-CoV-1 (or other, antigenically similar CoV-1) has silently infected a significant proportion of the population, inducing “herd immunity” (see Blog #42) needs to be confirmed. Indeed, immunity against the infection or patterns of semi-immunity (capacity of the immune system to avoid severe infection) may be due to immune cell activity rather than chemical immune responses. Animal models suggest that the efficiency of T lymphocyte-mediated immune responses is also pivotal for controlling SARS-CoV infections (yet another immune paradox). Serological testing with polymerase-chain-reaction (RT-PCR) testing may be helpful for the diagnosis of suspected patients with and for the identification of asymptomatic infections.
There is currently no data on the specific role of either chemical or cellular immunity or innate immunity in patients recovering from COVID-19. T lymphocytes responsible for clinically relevant antiviral immune responses have a significant chance to be locally present in, or close to, respiratory epithelia. It is very possible that the exclusive detection of immune chemical working against SARS-CoV-2 leads to an underestimation of the anti-SARS-CoV-2 immune responses. It becomes plausible that, after infection by SARS-CoV-2, a sort of race decides the course of the events. Either a cellular innate immune response rapidly clears SARS-CoV-2 without any (or mild) clinical signs of infection or the virus causes a state of immunosuppression that debilitates and sometimes overwhelms the host’s (human) defense
As we mentioned in the last blog, viruses are not living cells or organisms. They are obligate parasites or nonliving organisms that lack metabolic machinery of their own to generate energy or synthesize proteins. Rather, they require a living host to exploit or infect (enter) so they can replicate to complete their life cycle (see Fig. 7.1 and Life Cycle). The invading virus uses either its genomic DNA or RNA to replicate in the host cell. Coronaviruses (CoV) are a family of RNA viruses that typically cause mild respiratory disease in humans thought to be driven by the spillover of bat-adapted CoVs into an intermediate host. The novel coronavirus (SARS-CoV-2) is a single positive-strand RNA virus poorly adapted to the human host. If it is transmitted to humans, it is generally associated with more severe clinical presentations. Also, if infection occurs (and subsequent mutations), it can be highly transmissible from person to person as SARS-CoV-2 has demonstrated.
Researchers have analyzed genomic data related to the overall molecular structure of the new coronavirus. Their testing has traced this novel coronavirus to a strain of Malaysian anteaters (pangolin) containing genomic regions that are very closely related to the human virus. Their analysis showed that the genome resembles that of a bat coronavirus discovered after the COVID-19 pandemic began. However, in “SARS-CoV-2 testing,” the binding region of the spike protein resembles the novel virus found in pangolins (anteaters). This provides additional evidence that the coronavirus that causes COVID-19 almost certainly originated in nature, most likely in bats with an intermediate animal (anteater or monkey?) host and ultimately transmitted to humans (“zoonotic spillover”).
This genetic information concludes that “coronaviruses clearly have the capacity to jump species boundaries and adapt to new hosts” (anthroponotic being reported between domestic and zoo animals). Most important among these findings is the receptor binding domain (spike protein) that dictates how the virus is able to attach and infect human cells. This comparative analysis of genomic data dispelled the postulate that the virus was laboratory constructed or was a “manipulated” virus. Rather, it promotes a lesson learned to reduce human exposure to wildlife and to ban the trade and consumption (e.g., “wet markets” in China) of wildlife.
The genomic data of the new coronavirus show that its spike protein contains some unique adaptations. One of these adaptations provides special ability of this coronavirus to bind to a specific protein on human cells called angiotensin-converting enzyme (ACE-2). Human ACE-2 is expressed in epithelial cells of the lung and serves as an entry receptor site for SARS-CoV-2 spike protein. Finally, an interesting finding was made among SARS-CoV-2-infected patients. Researchers found a haplotype (a group of genes inherited together from a single parent) on chromosome 12 that reduces the risk of severe Covid-19 infection. This genetic mutation is associated with about a 22% reduction in the relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2. This region includes proteins that activate enzymes (proteases) that are important during infections with RNA viruses. The genetic region involved affects the body’s immune response to RNA viruses such as the coronavirus. This is a mutation that has been passed down over the millennia because it is assumed to help people survive the frequent viral infections among humans.
Blog #37: Immunology’s role in pandemics, infectious disease and COVID-19 (Part 3: It hurts and it kills)
Reported illnesses with the novel coronavirus have ranged from mild symptoms to severe illness and death. The symptoms may appear 2 to 14 days after exposure (based on the incubation period). As with any infectious disease, the array of symptoms can vary considerably, but there are eight cardinal symptoms in adults and children (and other possibilities) which are the defining complex of the clinical disease (Table 7.1). Elderly and immune-compromised patients are at greater risk of contracting the virus and for poor outcomes. However, significant numbers of young and healthy people are also being reported with severe infections, though generally with better outcomes. Spread occurs through respiratory droplets produced when an infected person coughs or sneezes. These droplets can land in the mouths or noses of people who are nearby or possibly be inhaled into the lungs.
Older age, obesity, and comorbidities have consistently been reported as the greatest risk factors for unfavorable prognosis or protracted disease, called “post-COVID syndrome,” “long COVID,” or “long haulers syndrome.” This syndrome, however, is found in a full range of COVID-19 patients, with symptomatology ranging from severe to nonexistent. The syndrome itself includes all sorts of problems with inflammatory responses in the brain (“brain fog”), around the heart (myocarditis), around the nerves (neuropathies), around the muscles (myosititis), etc. It’s clear that in addition to the immediate clinical effects of SARS-CoV-2, the novel coronavirus can have long-term manifestations, experts say. Less clear so far has been how the number and types of comorbidities influence outcomes.
All positive patients should be quarantined for up to 14 days. Some indirect biomarkers are being identified as diagnostic indicators for the degree and severity of a SARS-CoV-2 infection. Malfunction of interferon (IFN-1) was identified as attributing to an increase of at least 3.5% of patients with a life-threatening disease. Other studies of elevated concentrations of inflammatory cytokines and blood markers including C reactive protein, lactate dehydrogenase, and other digestive enzymes demonstrating that the gut microbiome is linked with the severity of COVID-19. The gut microbiota dysbiosis (imbalance) after disease resolution can also contribute to persistent symptoms (“long COVID”).
Diagnostic tests for COVID-19 infection include an "antigen test" that reveals if a person is actively infected with the SARS-CoV-2 virus. The test detects certain proteins that are part of the virus. Antigen tests aren’t as sensitive as molecular tests, but are readily available. A molecular genetic test (PCR test) detects the genetic material of the virus using a lab technique called polymerase chain reaction (PCR). Molecular tests are considered very accurate (kind of the gold standard) when properly performed by trained personnel. Antibody tests check a person’s blood by looking for antibodies, that may (or may not) tell if the person had a past infection with the coronavirus.
Neutralizing antibodies are specific to an antigen (the virus) and thus provide protection only against the specific disease associated with the virus. If the person is exposed to the antigen again, the antibodies produce “memory” toward the disease (remember the Bm cells and anamnestic protection from back in Blog #5?). There are however increasing reports of reinfection with the novel coronavirus suggesting that some coronavirus antibodies may not be neutralizing.
Finally, genome sequencing is essentially determining the order of chemical “bases” of a DNA molecule (see Blog #10). Next generation sequencing (NGS) efforts in the early stages of COVID-19 helped determine the structure of the virus, as well as its early mutations that increased transmissibility and produced a massive pandemic. Genome sequencing is essential in identifying, dealing with, and tracking the spread of the newly emerging and increasingly virulent and transmissible SARS-CoV-2 variants. Such transmissibility suggests that these variants are already widespread. With enough mutations, a strain may be able to evade current vaccines. If a vaccine-resistant strain is identified in the future, vaccine research will have to be directed towards a "universal vaccine" through evidence-based data. That evidence will only come from genome sequencing, AI and big data analytics.