How can a virus be determined to cause a disease?

How can a virus be determined to cause a disease?

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How can a virus be determined to cause a disease? From other posts I have read here, humans carry hundreds of different strains of viruses. How is a study structured and carried out to determine that one virus is the cause of a disease, and not any of the other viruses present? Any examples of studies are greatly appreciated as well.

A modified form of Koch's postulates is used to guide experiments that establish that a particular virus causes disease.

As a specific example of such a study, the SARS-CoV virus was determined to cause the SARS disease by fulfilling these criteria:

  1. SARS virus is found in people suffering from SARS, and not found in those who are healthy.
  2. The virus can be isolated from infected people and grown in cell cultures (here, Vero cells).
  3. Viruses grown in culture can be reisolated and compared with (and found identical to) the suspected pathogenic virus.
  4. This isolated virus can re-infect people (or infect model organisms; in this case, a species of macaques).
  5. Virus in reinfected organisms can be isolated, grown in culture, and found identical to the original pathogen.
  6. The immune system is observed to respond in similar ways to the infection (pneumonia and lung tissue lesions).

Anatomy and Structure of Viruses

Scientists have long sought to uncover the structure and function of viruses. Viruses are unique in that they have been classified as both living and nonliving at various points in the history of biology. Viruses are not cells but non-living, infectious particles. They are capable of causing a number of diseases, including cancer, in various different types of organisms.

Viral pathogens not only infect humans and animals, but also plants, bacteria, protists, and archaeans. These extremely tiny particles are about 1,000 times smaller than bacteria and can be found in almost any environment. Viruses can not exist independently of other organisms as they must take over a living cell in order to reproduce.

Steps of Virus Infections

A virus must use cell processes to replicate. The viral replication cycle can produce dramatic biochemical and structural changes in the host cell, which may cause cell damage. These changes, called cytopathic (causing cell damage) effects, can change cell functions or even destroy the cell. Some infected cells, such as those infected by the common cold virus known as rhinovirus, die through lysis (bursting) or apoptosis (programmed cell death or “cell suicide”), releasing all progeny virions at once. The symptoms of viral diseases result from the immune response to the virus, which attempts to control and eliminate the virus from the body, and from cell damage caused by the virus. Many animal viruses, such as HIV (human immunodeficiency virus), leave the infected cells of the immune system by a process known as budding, where virions leave the cell individually. During the budding process, the cell does not undergo lysis and is not immediately killed. However, the damage to the cells that the virus infects may make it impossible for the cells to function normally, even though the cells remain alive for a period of time. Most productive viral infections follow similar steps in the virus replication cycle: attachment, penetration, uncoating, replication, assembly, and release (Figure 1).


A virus attaches to a specific receptor site on the host cell membrane through attachment proteins in the capsid or via glycoproteins embedded in the viral envelope. The specificity of this interaction determines the host—and the cells within the host—that can be infected by a particular virus. This can be illustrated by thinking of several keys and several locks, where each key will fit only one specific lock.

Link to Learning

This video explains how influenza attacks the body.


The nucleic acid of bacteriophages enters the host cell naked, leaving the capsid outside the cell. Plant and animal viruses can enter through endocytosis, in which the cell membrane surrounds and engulfs the entire virus. Some enveloped viruses enter the cell when the viral envelope fuses directly with the cell membrane. Once inside the cell, the viral capsid is degraded, and the viral nucleic acid is released, which then becomes available for replication and transcription.

Replication and Assembly

The replication mechanism depends on the viral genome. DNA viruses usually use host cell proteins and enzymes to make additional DNA that is transcribed to messenger RNA (mRNA), which is then used to direct protein synthesis. RNA viruses usually use the RNA core as a template for synthesis of viral genomic RNA and mRNA. The viral mRNA directs the host cell to synthesize viral enzymes and capsid proteins, and assemble new virions. Of course, there are exceptions to this pattern. If a host cell does not provide the enzymes necessary for viral replication, viral genes supply the information to direct synthesis of the missing proteins. Retroviruses, such as HIV, have an RNA genome that must be reverse transcribed into DNA, which then is incorporated into the host cell genome. They are within group VI of the Baltimore classification scheme. To convert RNA into DNA, retroviruses must contain genes that encode the virus-specific enzyme reverse transcriptase that transcribes an RNA template to DNA. Reverse transcription never occurs in uninfected host cells—the needed enzyme reverse transcriptase is only derived from the expression of viral genes within the infected host cells. The fact that HIV produces some of its own enzymes not found in the host has allowed researchers to develop drugs that inhibit these enzymes. These drugs, including the reverse transcriptase inhibitor AZT, inhibit HIV replication by reducing the activity of the enzyme without affecting the host’s metabolism. This approach has led to the development of a variety of drugs used to treat HIV and has been effective at reducing the number of infectious virions (copies of viral RNA) in the blood to non-detectable levels in many HIV-infected individuals.


The last stage of viral replication is the release of the new virions produced in the host organism, where they are able to infect adjacent cells and repeat the replication cycle. As you’ve learned, some viruses are released when the host cell dies, and other viruses can leave infected cells by budding through the membrane without directly killing the cell.

Art Connection

Figure 1. In influenza virus infection, glycoproteins attach to a host epithelial cell. As a result, the virus is engulfed. RNA and proteins are made and assembled into new virions.

Influenza virus is packaged in a viral envelope that fuses with the plasma membrane. This way, the virus can exit the host cell without killing it. What advantage does the virus gain by keeping the host cell alive?

The host cell can continue to make new virus particles.

Link to Learning

Click through a tutorial on viruses, identifying structures, modes of transmission, replication, and more.

Molecular Koch&rsquos Postulates

In 1988, Stanley Falkow (1934&ndash) proposed a revised form of Koch&rsquos postulates known as molecular Koch&rsquos postulates. These are listed in the left column of Table (PageIndex<1>). The premise for molecular Koch&rsquos postulates is not in the ability to isolate a particular pathogen but rather to identify a gene that may cause the organism to be pathogenic.

Falkow&rsquos modifications to Koch&rsquos original postulates explain not only infections caused by intracellular pathogens but also the existence of pathogenic strains of organisms that are usually nonpathogenic. For example, the predominant form of the bacterium Escherichia coli is a member of the normal microbiota of the human intestine and is generally considered harmless. However, there are pathogenic strains of E. coli such as enterotoxigenic E. coli (ETEC) and enterohemorrhagic E. coli (O157:H7) (EHEC). We now know ETEC and EHEC exist because of the acquisition of new genes by the once-harmless E. coli, which, in the form of these pathogenic strains, is now capable of producing toxins and causing illness. The pathogenic forms resulted from minor genetic changes. The right-side column of Table (PageIndex<1>) illustrates how molecular Koch&rsquos postulates can be applied to identify EHEC as a pathogenic bacterium.

Table (PageIndex<1>): Molecular Koch&rsquos Postulates Applied to EHEC
Molecular Koch&rsquos Postulates Application to EHEC
(1) The phenotype (sign or symptom of disease) should be associated only with pathogenic strains of a species. EHEC causes intestinal inflammation and diarrhea, whereas nonpathogenic strains of E. coli do not.
(2) Inactivation of the suspected gene(s) associated with pathogenicity should result in a measurable loss of pathogenicity. One of the genes in EHEC encodes for Shiga toxin, a bacterial toxin (poison) that inhibits protein synthesis. Inactivating this gene reduces the bacteria&rsquos ability to cause disease.
(3) Reversion of the inactive gene should restore the disease phenotype. By adding the gene that encodes the toxin back into the genome (e.g., with a phage or plasmid), EHEC&rsquos ability to cause disease is restored.

As with Koch&rsquos original postulates, the molecular Koch&rsquos postulates have limitations. For example, genetic manipulation of some pathogens is not possible using current methods of molecular genetics. In a similar vein, some diseases do not have suitable animal models, which limits the utility of both the original and molecular postulates.

Explain the differences between Koch&rsquos original postulates and the molecular Koch&rsquos postulates.


Figure 1: The influenza reproductive cycle. In influenza virus infection, glycoproteins on the capsid attach to a host epithelial cell. Following this, the virus is engulfed. RNA and proteins are then made and assembled into new virions.

Influenza virus is packaged in a viral envelope that fuses with the plasma membrane. This way, the virus can exit the host cell without killing it. What advantage does the virus gain by keeping the host cell alive?

The host cell can continue to make new virus particles.


Diseases of livestock can be exceedingly interesting models to study virus emergence, given that harmonised international surveillance systems and regulatory frameworks provide opportunities to access field samples with associated metadata across national borders. Here, the BTV-8 European outbreaks provided us with the opportunity to investigate the mechanisms surrounding arbovirus emergence based on a uniquely rich dataset. Our results indicate that the re-emergence of BTV-8 in France in 2015 was caused by a virus that exhibits a lack of evolutionary changes since the first outbreak. This is inconsistent with the prevalent view of undetected low-level circulation of the virus in wild or domestic ruminants between 2010 and 2015, and instead points to another mechanism of emergence.

We showed a large discontinuity in the number of mutations accumulated by BTV-8 between 2010 and 2015, even though the evolutionary rates of the virus during the first and second outbreak were indistinguishable and of the same order as rates reported in previous BTV studies [39,40]. If the virus had been replicating consistently in an undetected population from 2010 to 2015, we would expect the genetic distance of the isolates from the second European outbreak to continue the trend of increased divergence after the first outbreak. However, the sequences from the second outbreak exhibit genetic divergences that fall considerably below what would be expected if the trend line from the first outbreak was extended, illustrating a paucity of mutations (Fig 4B). Indeed, the divergence of the reconstructed ancestor of the second bluetongue outbreak is consistent with the virus stopping replication in March 2008. The lack of divergence is also illustrated by the fact that the reconstructed ancestor of the BTV-8 outbreak has only 7 mutations separating it from its closest relative in the analysed dataset, a French sample collected in August 2007 (BTV-8FRA2007-3673), despite putatively having been replicating for at least half a decade after that sample’s collection. In comparison, BTV-8FRA2007-3673 showed 23 mutations compared to the genome of the earliest BTV-8 sample obtained from the Netherlands in August 2006, only a year earlier. The corresponding rate of evolution estimated for the emerging branch was almost an order of magnitude slower than the mean clock rate, highlighting it as exceptionally low (Fig 3). Moreover, we hypothesise that some or all of the estimated seven mutations on this branch might have accumulated during the first outbreak, given that the emerging branch connects to an internal node in the timescaled phylogeny with a date of early 2007, at the height of the first outbreak. The subsequent accumulation of seven mutations is consistent with the idea that this virus continued to circulate until early 2008 (the inferred date from the root-to-tip regression) and then ceased to change altogether until its re-emergence in 2015. While previous studies have found apparent evolutionary stasis to be the result of mislabelling [41], this can be ruled out in our case due to the discontinuity applying to all samples from the second outbreak, not just a single isolate. Another hypothetical scenario could be envisaged if BTV-8 was to remain “latent” in midges’ eggs for a number of years. However, there is no evidence of vertical transmission in BTV-infected Culicoides [42–45]. This, in conjunction with the need for infected midge eggs to survive for years, rather than a single overwintering season, makes this scenario highly unlikely.

Given the unexpectedly low number of mutations observed between the two outbreaks, our data indicate that the common ancestor of the second European outbreak either ceased or dramatically slowed its replication in early 2008. This is inconsistent with current knowledge and paradigms of the biology of BTV and RNA viruses in general. For example, a potential explanation could be that BTV persistently infected a host for several (5 to 8) years, with little or no replication, before being reactivated and starting the second outbreak. While this may be possible with DNA viruses, or RNA viruses with a DNA intermediate [46–51], a mechanism for this has never been described before for reoviruses such as BTV and in general for other RNA viruses.

Our findings have interesting parallels to puzzling examples from other RNA viruses, such as two Ebola virus outbreaks in the Democratic Republic of Congo in 2014 and 2018 [52,53]. Isolates from both outbreaks were minimally divergent from isolates collected about a decade earlier, resulting in a far lower evolutionary rate than other known lineages. It has been suggested that such slow evolution may be caused by the maintenance of the virus in an animal reservoir, where infection might be associated with lower replication rates compared to human hosts [52,53]. Rabies virus may provide an additional peculiar example based on a handful of reports in human patients of virus reactivation after latency of several years [54], but it has not been documented whether these cases involved a lack of evolutionary changes. In other cases, such as foot-and-mouth disease, viral RNA and infectious virus have been shown to persist in reservoir hosts for multiple years. However, re-isolation of virus (as opposed to detection of viral RNA) indicates that the virus replicates during persistent infection and accumulates nucleotide substitutions at a rate comparable to actively replicating viruses [55,56]. Hepatitis C virus, for example, is also known to persist in a number of patients for a number of years but, again, with continuing viraemia and thus virus replication [57].

Overall, we judge the possibility of persistence of BTV-8 in a mammalian or invertebrate host for longer than five years, in the absence of viral replication, followed by viral reactivation and subsequent onwards spread, to be unlikely given the current understanding of RNA virus biology. We hypothesise that accidental release of frozen material contaminated with BTV-8 could be the cause of the virus re-emergence in France in 2015. Anthropogenic causes of virus outbreaks have been described before. Accidental virus release is thought to have been responsible for the 1977 influenza A H1N1 outbreak, caused by a virus that closely matched a variant circulating in the 1950s [58,59] likewise, the 1995 Venezuelan equine encephalitis subtype IC epidemic was caused by a virus closely related to a strain circulating in 1962–1964 [60]. For livestock pathogens, a localised outbreak of foot-and-mouth disease virus (FMDV) in the United Kingdom in 2007 was linked to virus escaped from research facilities [61].

Our data cannot reveal the actual source from which BTV-8 was re-introduced in France in 2015. We speculate that laboratory escape of virus preparations, such as the case of FMDV in the UK in 2007, is unlikely, as BTV needs an insect vector for efficient transmission and we are unaware of any in vivo insect experiments in France with BTV during that period. However, due to specific animal husbandry procedures, there are important potential sources of frozen virus that apply to viruses of livestock and not viruses of most other animals, specifically the widespread use of bull semen for artificial insemination and embryo transfer in cows [62,63]. BTV has been detected in the semen of viraemic bulls and rams, can initiate infection in the mother, and can be transmitted vertically to the embryo [64,65]. Additionally, contaminated embryos can cause transmission on implantation [66]. As such, both semen and embryos may represent potential sources of BTV infection. Contaminated frozen colostrum may also be a potential source, considering that oral transmission has been shown to be possible with BTV-8 [67]. However, it is not normal practice to keep colostrum frozen for a number of years. Interestingly, while international regulations specify that bull donors and semen that are exported internationally must be screened for various pathogens including BTV [68], this does not apply to premises trading only locally and carrying out private insemination procedures [69]. Thus, semen from a BTV-8–infected bull could have been collected or an embryo generated from an infected but asymptomatic animal and used years later without detection.

We stress that the link between bull semen trade and embryo implantation in France and the BTV-8 re-emergence in 2015 is only speculative. However, we have shown that the re-emergence of BTV-8 in France in 2015 is unlikely to be due to cryptic continuing transmission, and we can exclude a reintroduction from another endemic country. Thus, our data are incompatible with the two current dominant theories for explaining the 2015 outbreak [31]. The lack of accumulated mutations in the virus implies that there was either an ongoing persistent infection in the absence of viral replication for several years, or the virus originated from material that had been frozen during the first outbreak. We argue the second of these explanations to be more likely. Our findings highlight new areas requiring thorough surveillance programmes for the control of infectious disease of livestock. In addition, our approach illustrates how unrecognised pathways of disease emergence can be revealed using pathogen genomic epidemiology.

21.3: Prevention and Treatment of Viral Infections

Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis . These diseases can be treated by antiviral drugs or by vaccines, but some viruses, such as HIV, are capable of both avoiding the immune response and mutating to become resistant to antiviral drugs.

Review Questions

Which of the following is NOT used to treat active viral disease?

  1. are similar to viroids
  2. are only needed once
  3. kill viruses
  4. stimulate an immune response

Free Response

Why is immunization after being bitten by a rabid animal so effective and why aren&rsquot people vaccinated for rabies like dogs and cats are?

Rabies vaccine works after a bite because it takes week for the virus to travel from the site of the bite to the central nervous system, where the most severe symptoms of the disease occur. Adults are not routinely vaccinated for rabies for two reasons: first, because the routine vaccination of domestic animals makes it unlikely that humans will contract rabies from an animal bite second, if one is bitten by a wild animal or a domestic animal that one cannot confirm has been immunized, there is still time to give the vaccine and avoid the often fatal consequences of the disease.

Study: Viruses Are Living Entities, Not Machines

Giant Acanthamoeba-infecting virus Pandoravirus salinus. Image credit: © IGS CNRS-AMU.

“Until now, viruses have been difficult to classify. In its latest report, the International Committee on the Taxonomy of Viruses recognized seven orders of viruses, based on their shapes and sizes, genetic structure and means of reproducing,” said co-author Prof. Gustavo Caetano-Anollés of the University of Illinois.

“Under this classification, viral families belonging to the same order have likely diverged from a common ancestral virus. However, only 26 of 104 viral families have been assigned to an order, and the evolutionary relationships of most of them remain unclear.”

Part of the confusion stems from the abundance and diversity of viruses. Less than 4,900 viruses have been identified and sequenced so far, even though scientists estimate there are more than a million viral species.

Many viruses are very small and contain only a handful of genes. Others, like recently discovered Acanthamoeba-infecting viruses (Pithovirus, Mollivirus, Mimiviruses and Pandoraviruses), are huge, with genomes bigger than those of some bacteria.

The new study focused on the vast repertoire of protein structures, called ‘folds,’ that are encoded in the genomes of all cells and viruses. By comparing fold structures across different branches of the tree of life, scientists can reconstruct the evolutionary histories of the folds and of the organisms whose genomes code for them.

Prof. Caetano-Anollés and his colleague, Arshan Nasir, also from the University of Illinois, chose to analyze protein folds because the sequences that encode viral genomes are subject to rapid change.

“Their high mutation rates can obscure deep evolutionary signals. Protein folds are better markers of ancient events because their 3D structures can be maintained even as the sequences that code for them begin to change,” Prof. Caetano-Anollés said.

Today, many viruses – including those that cause disease – take over the protein-building machinery of host cells to make copies of themselves that can then spread to other cells. Viruses often insert their own genetic material into the DNA of their hosts. In fact, the remnants of ancient viral infiltrations are now permanent features of the genomes of most cellular organisms, including humans.

“This knack for moving genetic material around may be evidence of viruses’ primary role as spreaders of diversity,” Prof. Caetano-Anollés said.

The team analyzed all of the known folds in 5,080 organisms representing every branch of the tree of life, including 3,460 viruses.

Using advanced bioinformatics methods, they identified 442 protein folds that are shared between cells and viruses, and 66 that are unique to viruses.

“This tells you that you can build a tree of life, because you’ve found a multitude of features in viruses that have all the properties that cells have. Viruses also have unique components besides the components that are shared with cells,” Prof. Caetano-Anollés said.

The new study uses protein folds as evidence that viruses are living entities that belong on their own branch of the tree of life. Image credit: Julie McMahon.

The analysis revealed genetic sequences in viruses that are unlike anything seen in cells. This contradicts one hypothesis that viruses captured all of their genetic material from cells.

“This and other findings also support the idea that viruses are creators of novelty,” Caetano-Anollés said.

The researchers used computational methods to build trees of life that included viruses.

“The data suggest that viruses originated from multiple ancient cells and co-existed with the ancestors of modern cells. These ancient cells likely contained segmented RNA genomes,” Prof. Caetano-Anollés said.

“The data also suggest that at some point in their evolutionary history, not long after modern cellular life emerged, most viruses gained the ability to encapsulate themselves in protein coats that protected their genetic payloads, enabling them to spend part of their lifecycle outside of host cells and spread.”

The protein folds that are unique to viruses include those that form these viral capsids. These capsids became more and more sophisticated with time, allowing viruses to become infectious to cells that had previously resisted them. This is the hallmark of parasitism,” Nasir said.

“Some scientists have argued that viruses are nonliving entities, bits of DNA and RNA shed by cellular life. They point to the fact that viruses are not able to replicate outside of host cells, and rely on cells’ protein-building machinery to function. But much evidence supports the idea that viruses are not that different from other living entities,” Prof. Caetano-Anollés said.

Many organisms require other organisms to live, including bacteria that live inside cells, and fungi that engage in obligate parasitic relationships – they rely on their hosts to complete their lifecycle. And this is what viruses do.

“The lack of translational machinery in viruses was once cited as a justification for classifying them as nonliving. This is no more. Viruses now merit a place in the tree of life. Obviously, there is much more to viruses than we once thought,” Prof. Caetano-Anollés concluded.

Arshan Nasir & Gustavo Caetano-Anollés. 2015. A phylogenomic data-driven exploration of viral origins and evolution. Science Advances, vol. 1, no. 8, e1500527 doi: 10.1126/sciadv.1500527


Remember the last time you had a sore throat, fever, or cough? There is a good chance that you felt sick because your body was fighting a virus, a tiny invader that uses your cells to copy itself. Viruses can infect every known living thing. Animals, plants, and even bacteria catch viruses. Bacteria or viruses that make other living things sick are called pathogens.

Even though we try to stay away from pathogens, many other bacteria and viruses are helpful. Bacteria that live in the oceans and soil are important to cycle nutrients in the environment. Other bacteria turn milk into yogurt or cheese for us to eat.

There are even some helpful viruses and bacteria that live inside you, called mutualists. Some viruses and bacteria inside you actually help guard your body against more dangerous infections, and other viruses can help plants survive cold or droughts better. Bacteria in your gut help you digest your food and make vitamins you can’t make yourself.

If we were able to see viruses with our eyes, we would see that they are all around us. Luckily, your immune system can remove most viruses that make you sick. In some cases, doctors give us medicines that can slow down difficult viruses to help your immune system fight them.

The coronavirus isn’t alive. That’s why it’s so hard to kill.

Please Note

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Viruses have spent billions of years perfecting the art of surviving without living — a frighteningly effective strategy that makes them a potent threat in today’s world.

That’s especially true of the deadly new coronavirus that has brought global society to a screeching halt. It’s little more than a packet of genetic material surrounded by a spiky protein shell one-thousandth the width of an eyelash, and it leads such a zombielike existence that it’s barely considered a living organism.

But as soon as it gets into a human airway, the virus hijacks our cells to create millions more versions of itself.

There is a certain evil genius to how this coronavirus pathogen works: It finds easy purchase in humans without them knowing. Before its first host even develops symptoms, it is already spreading its replicas everywhere, moving onto its next victim. It is powerfully deadly in some but mild enough in others to escape containment. And for now, we have no way of stopping it.

As researchers race to develop drugs and vaccines for the disease that has already sickened 350,000 and killed more than 15,000 people, and counting, this is a scientific portrait of what they are up against.

‘Between chemistry and biology’

Respiratory viruses tend to infect and replicate in two places: In the nose and throat, where they are highly contagious, or lower in the lungs, where they spread less easily but are much more deadly.

This new coronavirus, SARS-CoV-2, adeptly cuts the difference. It dwells in the upper respiratory tract, where it is easily sneezed or coughed onto its next victim. But in some patients, it can lodge itself deep within the lungs, where the disease can kill. That combination gives it the contagiousness of some colds, along with some of the lethality of its close molecular cousin SARS, which caused a 2002-2003 outbreak in Asia.

Another insidious characteristic of this virus: By giving up that bit of lethality, its symptoms emerge less readily than those of SARS, which means people often pass it to others before they even know they have it.