*Coronaviruses: An Overview of Their Replication and Pathogenesis
Anthony R. Fehr and Stanley Perlman Department of Microbiology,
University of Iowa Carver College of Medicine, Iowa City, IA 52242
Coronaviruses (CoVs), enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, an unusually large RNA genome, and a unique replication strategy. Coronaviruses cause a variety of diseases in mammals and birds ranging from enteritis in cows and pigs and upper respiratory disease chickens to potentially lethal human respiratory infections. Here we provide a brief introduction to coronaviruses discussing their replication and pathogenicity, and current prevention and treatment strategies. We will also discuss the outbreaks of the highly pathogenic Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently identified Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV). Full PDF of article here…
A Little Knowledge – Too Much Knowledge
They say a little knowledge is a bad thing. But what about too much knowledge? About pandemics. About viruses. I was a pre-Med student. I worked in a free clinic doing what were known as VDRLs and RBC/WBC routinely. I had no certification at the time, just the desire to help. You didn’t need it at the time. There were no free clinics or HMOs, or anything in those days. There were barely ambulances and no 9-1-1. That was in college in the 1970’s. In the 1970’s, our patients at the free clinic were working people. A bus driver who was feeling giddy, head-aches, and out-of-sorts for weeks. Turned out he had lead poisoning from the fumes of his bus (yep gasoline, as bad as it is today, was worse in the 1970’s). A “society lady” who had had an illegal abortion by a criminal syndicate doctor in the back of a Caddy going down Lake Shore Drive one night and became infected. That sort of thing. I later became an NREMT, WEMT, and WMI Instructor of EM for 15 years. I was a volunteer at art festivals and part of Benton County Fire One in the rural areas of Washington State. As a punk kid, I had contracted the 1957 Pandemic Influenza A (wave 1). Three strains they believed I contracted, two of which they identified as H2N2 and a variant H2N3. I was placed in isolation at the new Seattle Children’s for a week, living off of a glucose drip and no solid food, with my parents wearing masks and wondering if I would survive as they looked down. Eventually, that Influenza A killed over one million people World-wide. Dad had been more optimistic for me. He had survived the Spanish Influenza A (H1N1) as a 5-year old, like me catching it early in the “null” wave of Fall of 1917. It went on to have three subsequent waves; the second one striking the USA after the first, with a certain vengeance. At least that is how Dad remembered it. Eventually, it killed over twenty to fifty million people World-wide. That’s 20-50 MILLION people in three waves. So. I know. A little about edicine. And a lot about pandemics. A virus does not generate a pandemic or is named a “pandemic” easily. It must be special.
This is one of the first pandemic caused by a coronavirus, not an Influenza A. The coronavirus is a mRNA (messenger RNA). Its replication pathway is a contorted and somewhat unusual according to some articles. Its RNA is HUGE. Truly HUGE (~310 kDa). Those red spikes on the surface are one of its only protein structure. It has four and sometimes five proteins. That red thing is called the “Spike” protein (S). It also has an H(E) protein and an N(1) protein variant. From what I can tell from the literature, this coronavirus has been with us for a l-o-n-g time. Yet, it was never considered a threat, as the variants that appeared pathogenic were self mediating. In other words, patients infected with them, built immunity and survived. The RNA replicant strings did not mutate fast enough or at all, to keep up with most human immune responses. These were and are the “alpha-” variety. Then came the “beta-” variety. They have a section of the replicant string that changes rapidly. They made their appearance in the early 2010’s. These are the SAR-CoV and MERS-CoV types. These were documented in 2016, in an excellent article.* As I write this, The Chinese medical establishment is tracing back the most recent coronavirus origins. It appears that, like all previous pandemics, it began quietly. In November, 2019. A 51-year old man was afflicted and did not easily recover. Doctors treating him thought it was SAR at first, but he developed no headaches, only severe fever and pneumonia. This must have been the “null” wave. After that, sporadic reports, as the virus went global. Then it struck again in January, 2020 with greater severity in Wuhan and took the World by surprise. Deaths were reported. The virus was already mutating and was global. That is the First Wave.
Humans aren’t Special
One of the least discussed or understood for that matter, but most significant attributes of past pandemics is this. Once a pathogenic virus was spread from avian to mammal then to humans, humans were able to spread it back to mammals to become even more lethal in humans during The Second Wave. There have been more than one report of SARS-CoV-2 in dogs in China and elsewhere already. As one example of this from the past, the N1H1 Influenza A in the 1918 pandemic was believed to spread from avian/pig origins to humans. What was little known until decades later was that it then went through an evolution of sorts in Midwest swines. Quoting from the CDC report…
“The origin of this pandemic has always been disputed and may never be resolved. However, the observations of trained observers at that time are worth noting because they may bear on later genomic analysis of the recently resurrected 1918 virus nucleotide fragments and the abortive “swine flu” epidemic of 1976. In Richard Shope’s Harvey lecture of 1936, he reviews evidence that in the late summer or early autumn of 1918, a disease not previously recognized in swine, and closely resembling influenza in humans, appeared in the American Middle West.
Epidemiologic-epizootiologic evidence strongly suggested that the causative virus was moving from humans to swine rather than in the reverse direction. “Similar observations were made on the other side of the world and reported in a little-known paper in the National Medical Journal of China.
In the spring of 1918, influenza in humans spread rapidly all over the world and was prevalent from Canton, China, to the most northern parts of Manchuria and from Shanghai to Szechuan. In October 1918, a disease diagnosed as influenza appeared in Russian and Chinese pigs in the area surrounding Harbin. Thus, epidemiologic evidence, fragmentary as it is, appears to favor the spread of virus from humans to swine, in which it remained relatively unchanged until it was recovered more than a decade later by Dr. Shope in the first isolation of influenza virus from a mammalian species….”
Present Pandemic Pathogenesis
“Coronaviruses cause a large variety of diseases in animals, and their ability to cause severe disease in livestock and companion animals such as pigs, cows, chickens, dogs and cats led to significant research on these viruses in the last half of the 20th century.
For instance, Transmissible Gastroenteritis Virus (TGEV) and Porcine Epidemic Diarrhea Virus (PEDV) cause severe gastroenteritis in young piglets, leading to significant morbidity, mortality, and ultimately economic losses. PEDV recently emerged in North America for the first time, causing significant losses of young piglets. Porcine hemagglutinating encephalomyelitis virus (PHEV) mostly leads to enteric infection but has the ability to infect the nervous system, causing encephalitis, vomiting and wasting in pigs. Feline enteric coronavirus (FCoV) causes a mild or asymptomatic infection in domestic cats, but during persistent infection, mutation transforms the virus into a highly virulent strain of FCoV (Feline Infectious Peritonitis Virus, FIPV), that leads to development of a lethal disease called feline infectious peritonitis (FIP). FIP has wet and dry forms, with similarities to the human disease, sarcoidosis. FIPV is macrophage tropic and it is believed that it causes aberrant cytokine and/or chemokine expression and lymphocyte depletion, resulting in lethal disease. However additional research is needed to confirm this hypothesis. Bovine CoV, Rat CoV, and Infectious Bronchitis Virus (IBV) cause mild to severe respiratory tract infections in cattle, rats, and chickens, respectively. Bovine CoV causes significant losses in the cattle industry and also has spread to infect a variety of ruminants, including elk, deer and camels. In addition to severe respiratory disease, the virus causes diarrhoea (‘winter dysentery’ and ‘shipping fever’), all leading to weight loss, dehydration, decreased milk production, and depression. Some strains of IBV, a γ-coronavirus, also affect the uro-genital tract of chickens causing renal disease. IBV significantly diminishes egg production and weight gain, causing substantial losses in the chicken industry each year. More recently, a novel coronavirus named SW1 was identified in a deceased Beluga whale.
“Large numbers of virus particles were identified in the liver of the deceased whale with respiratory disease and acute liver failure. Although, electron microscopic images were not sufficient to identify the virus as a coronavirus, sequencing of the liver tissue clearly identified the virus as a coronavirus. It was subsequently determined to be a γ-coronavirus based on phylogenetic analysis but it has not yet been verified experimentally that this virus is actually a causative agent of disease in whales. In addition, there has been intense interest in identifying novel bat CoVs, since these are the likely ultimate source for SARS-CoV and MERS-CoV, and hundreds of novel bat coronaviruses have been identified over the past decade. Finally, another novel group of nidoviruses, Mesoniviridae, were recently identified as the first nidoviruses to exclusively infect insect hosts. These viruses are highly divergent from other nidoviruses but are most closely related to the roniviruses. In size, they are ∼20 kb, falling in between large and small nidoviruses. Interestingly, these viruses do not encode for an endoribonuclease, which is present in all other nidoviruses. These attributes suggest these viruses are the prototype of a new nidovirus family and may be a missing link in the transition from small to large nidoviruses.
“The most heavily studied animal coronavirus is murine hepatitis virus (MHV), which causes a variety of outcomes in mice, including respiratory, enteric, hepatic, and neurologic infections. These infections often serve as highly useful models of disease. For instance, MHV-1 causes severe respiratory disease in susceptible A/J and C3H/HeJ mice, A59 and MHV-3 induce severe hepatitis, while JHMV causes severe encephalitis. Interestingly, MHV-3 induces cellular injury through the activation of the coagulation cascade. Most notably, A59 and attenuated versions of JHMV cause a chronic demyelinating disease that bears similarities to multiple sclerosis (MS), making MHV infection one of the best models for this debilitating human disease. Early studies suggested that demyelination was dependent on viral replication in oligodendrocytes in the brain and spinal cord; however, more recent reports clearly demonstrate that the disease is immune-mediated. Irradiated mice or immunodeficient (lacking T and B cells) mice do not develop demyelination, but addition of virus-specific T cells restores the development of demyelination. Additionally, demyelination is accompanied by a large influx of macrophages and microglia that can phagocytose infected myelin, although it is unknown what the signals are that direct immune cells to destroy myelin. Finally, MHV can be studied under BSL2 laboratory conditions, unlike SARS-CoV or MERS-CoV, which require a BSL3 laboratory, and provides a large number of suitable animal models. These factors make MHV an ideal model for studying the basics of viral replication in tissue culture cells as well as for studying the pathogenesis and immune response to coronaviruses.
“Prior to the SARS-CoV outbreak, coronaviruses were only thought to cause mild, self- limiting respiratory infections in humans. Two of these human coronaviruses are α- coronaviruses (HCoV-229E and HCoV-NL63) while the other two are β-coronaviruses (HCoV-OC43 and HCoV-HKU1). HCoV-229E and HCoV-OC43 were isolated nearly 50 years ago while HCoV-NL63 and HCoV-HKU1 were only recently identified following the SARS-CoV outbreak. These viruses are endemic in the human populations, causing 15–30% of respiratory tract infections each year. They cause more severe disease in neonates, the elderly, and in individuals with underlying illnesses, with a greater incidence of lower respiratory tract infection in these populations.” *