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Viruses are parasites. The only way they can grow is by hijacking their hosts. When they infect a human host, viruses use human proteins to multiply and modify the human cells to sustain the infection. At the same time, the human host activates defense mechanisms to fight the infection.

Most current drugs against viral infections target the virus itself. But scientists are interested in developing therapies that aim for host proteins instead, or the genes that produce them, in part because such therapies are believed less likely to elicit drug resistance. A detailed understanding of virus-host interactions is crucial to the success of this strategy.

A team of Gladstone Institutes scientists led by Senior Investigator Nevan Krogan, PhD, has been cataloging host proteins that physically bind to virus proteins. These physical interactions identify human proteins that the virus can use to infect cells and propagate. However, they don't reveal how host proteins work together to facilitate infection.

To address this gap, Krogan and staff scientist David Gordon, PhD, with colleagues at UC San Francisco (UCSF), University College Dublin, and the Mount Sinai School of Medicine, have developed a new way to understand how host cells control HIV infection in human cells.

Their approach entails disrupting host genes rather than proteins. It is based on the idea, pioneered by Krogan, that you obtain richer information about the functions of genes–and the proteins they encode–when you disable the genes in pairs, instead of one by one. In a paper published in Molecular Cell, the team describes a map of the genes controlling HIV infection in human cells, which they built by assessing more than 63,000 combinations of human genes associated with HIV infection.

HIV is a major public health concern, with an estimated 36.7 million people living with chronic infection, and over 20.9 million people receiving continuous treatment. Studying the impact of gene disruptions in pairs rather than one by one yields important information on how genes work together to mediate virus infection, highlighting processes we can target with drugs to inhibit infection."

Nevan Krogan, Ph.D., senior investigator, professor of Cellular and Molecular Pharmacology at UCSF, and the director of the UCSF Quantitative Biosciences Institute

The map, which the team refers to as a viral epistasis map (vE-MAP), is an essential advance for HIV research in several other ways. For one thing, it uncovers a previously unsuspected set of genes required for the growth of the virus in human cells. For another, the vE-MAP can be used to analyze how different HIV mutants affect host cells or to test drugs that disrupt HIV-host interactions.

Strength in numbers

The vE-MAP is an adaptation of the E-MAP, which Krogan and his colleagues pioneered and refined over the past 15 years to identify genes that control how cells grow. At the core of this approach is the Krogan lab's ability to disrupt a large number of genes, test them in pairs, and analyze the results via sophisticated computational methods.

"The principle behind E-MAPs is that when you disrupt two genes at once and examine the impact on a cell, you sometimes see effects that are significantly larger or smaller than you would have predicted from the effect of disrupting either gene alone," said Krogan.

These unexpected effects suggest that the functions of the two genes are related. Moreover, by carrying out these pairwise disruptions across hundreds of genes, scientists can find groups of genes with similar patterns of interactions, a sign that they are likely to take part in the same molecular process.

"And so, instead of finding important genes one at a time, you can all at once identify multiple, distinct networks of genes affecting the process you are studying," said Gordon.

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The E-MAP approach has mostly been used to study cell growth. Gordon, in collaboration with a student from University College Dublin, Ariane Watson, had to modify it to study virus infection. The most tricky part was to implement a sophisticated data acquisition and scoring system, which allowed them to measure HIV infection accurately across hundreds of thousands of samples, and compare the effect of pairwise and single-gene disruptions.

It would be an overwhelming effort to test all combinations of the over 20,000 protein-coding genes in the human genome. Instead, the scientists focused on genes already suspected to influence HIV biology. In particular, they used the genes encoding a large number of human proteins that the Krogan lab had previously found to bind to HIV proteins. In all, they included over 350 genes in their analysis and tested over 63,000 pairwise disruptions.

New players at the HIV-host interface

Although HIV is one of the best-studied human viruses and is now well-controlled by antiretroviral therapy, there is no cure for HIV/AIDS. Moreover, antiretroviral therapy is costly, which can make it impractical in resource-poor countries. The search for new means of halting or eradicating the virus is, therefore, still a priority.

Among the genes that stood out in the vE-MAP were several members of the CNOT family, whose role in HIV biology had never before been established. The authors demonstrated that the CNOT complex promotes HIV infection by suppressing innate immunity in CD4+ T cells, the type of immune cells that HIV preferentially targets in humans. Innate immunity is a defense mechanism by which host cells can fight infection.

"The impact of CNOT on innate immunity is a key, yet previously unrecognized, host pathway critical to HIV infection. It will serve as a potential novel therapeutic target in future studies," said Krogan.

For instance, scientists can now study if targeting the CNOT complex with drugs could be a way to help HIV patients fight the infection more effectively.

Furthermore, the vE-MAP uncovered genes that had little impact when disrupted individually, but a great effect when tested together.

"These genes would be overlooked in classic, single-gene disruption experiments," said Gordon. "They confirm the potential of the vE-MAP to uncover new mechanisms by which HIV interacts with human cells."

Combining drugs that target two of these genes at the same time might thus be a promising therapeutic strategy, especially for a virus such as HIV/AIDS, which has evolved multiple ways of tapping its hosts' resources.

The vE-MAP was also able to pick up genes that specifically interact with a known HIV mutant. This observation bodes well for the ability of the vE-MAP to identify distinct host factors affecting the various forms of HIV, or the virus mutants that arise in response to currently available drugs.

Additional testing with a drug known to interfere with HIV-associated human proteins gives the authors confidence that their vE-MAP approach could, in the future, be used to screen for novel anti-HIV drugs and to understand their mode of action.

"This vE-MAP provides an unprecedented view of how HIV hijacks and rewires the cellular machinery in human cells during infection," said Krogan. "It will generate many new ideas and avenues to identify and test novel therapies."

And the benefits may not be limited to HIV research.

"Our work is proof-of-principle that the vE-MAP approach is a powerful way to map out the interface between HIV and human cells, and to uncover new therapeutic avenues," said Gordon. "We now look forward to testing it on other pathogens."

Source:

Gladstone Institutes

In just a matter of days, Italy has reported an increasing number of cases linked to the novel coronavirus that is spreading rapidly across the globe. The coronavirus disease (COVID-19) has emerged in China late in December 2019 and has so far reached 30 countries.

Italy has now reported 155 confirmed cases of the novel coronavirus, with three deaths. Meanwhile, other countries have issued travel warnings and stopped trains from Italy in fears of patients with the virus to enter their borders.

ITALY, BERGAMO- 22 February 2020: medical services at the airport Bergamo-Milano investigate aircraft passengers who have arrived in Italy to minimize the risk of the spread of the coronavirus epidemic. Image Credit: Grabowski Foto / Shutterstock

The Italian government announced that neither entry not exit to the Veneto and Lombardy regions is allowed without having special permission. Prime Minister Giuseppe Conte said the government is working to control the situation and prevent a large-scale outbreak in the country.

Authorities have been ordered to strictly monitor the entrance and exit of residents, with fines imposed on violators. Further, the education sector of the country has said that classes and academic activities in the affected regions would be suspended between Feb. 24 and 29.

In abundance of precaution, Austria has stopped all trains from and to Italy after two passengers manifested coronavirus-like symptoms. At the border, officials denied entry to a train from Venice to Munich on Feb. 23 in fear that the two passengers may be infected with the deadly virus.

The country has placed about 50,000 people under quarantine in the affected regions.

Coronavirus is spreading

The World Health Organization (WHO) increases efforts to contain the virus and prevent its spread to other countries, fearing that if it infects people in a country with a poor healthcare system, it can cause devastating results.

As of writing, there are 79,152  confirmed cases of the coronavirus disease (COVID-19), which has spiraled into a global threat. Most of the cases were reported in mainland China, particularly in the ground zero of the outbreak, Hubei Province. There are 2,470 deaths linked to the coronavirus, prompting countries to impose travel bans, quarantine millions of people, and isolating ill patients in an attempt to stem the spread of the deadly virus.

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On the Diamond Princess cruise ship in Japan, where more than 3,000 people where quarantined, the last passenger has left, but the risk of infection still lingers as the ship crew, and health officials are still onboard. Also, raised fears of the possibility of the virus still spreading exist as a woman who tested negative days prior has now developed coronavirus-like symptoms. She has tested positive after returning home to Tochigi prefecture north of Tokyo by train from the ship.

The health minister of Japan, Katsunobu Kato, has also apologized after 23 passengers were allowed to leave the ship without being adequately tested. He said they would trace the passengers and have them retested.

Meanwhile, four of the 32 passengers from the Diamond Princess cruise ship taken to Arrowe Park, Merseyside, UK, have tested positive for the coronavirus. The total number of passengers from Europe who tested positive is 13.

Hurtling into a pandemic

A pandemic, according to the WHO, a pandemic is the worldwide spread of a new disease.

Though the WHO has not declared the coronavirus outbreak a pandemic, it had raised concern when a sudden spike in cases was reported in South Korea, Italy, and Iran.

“The window of opportunity is still there, but the window of opportunity is narrowing. We need to act quickly before it closes completely,” Tedros Adhanom Ghebreyesus, WHO Director-General, said.

During the first weeks of the outbreak, health officials meticulously traced all the possible contacts of every person who becomes infected with the coronavirus. Everyone with close contact with the patient will be advised to self-quarantine for 14 days and will be closely monitored for any symptoms.

However, with the number of current infections reaching 80,000, contact tracing can become impractical. If the coronavirus becomes a pandemic, a large proportion of the population across the globe will become infected. Though the term pandemic sparks fear, it pertains to how wide is the spread of the outbreak, not how fatal it is.

If stopping the spread of the virus from spreading is increasingly out of reach, public health officials and health agencies will have to move on to a new stage – to prepare for a pandemic, by strengthening the healthcare system of countries, fast-tracking treatments and vaccines for the infection, and providing care for those who are already infected.

Sources:

World Health Organization (WHO). (2010). What is a pandemic?. https://www.who.int/csr/disease/swineflu/frequently_asked_questions/pandemic/en/

World Health Organization (WHO). (2020). Coronavirus disease 2019 (COVID-19) Situation Report – 34. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200223-sitrep-34-covid-19.pdf?sfvrsn=44ff8fd3_2

Back in February 2018, the World Health Organization (WHO) talked about a new virus that will emerge and wreak havoc across the globe. Disease X was the term used for this new unknown pathogen that might cause a future epidemic.

Two years later, the novel COVID-19 coronavirus, has evolved from a mild to deadly virus and is spreading across the globe. This begs the question, is COVID-19 the dreaded Disease X that the WHO predicted back in 2018?

Disease X is a placeholder name adopted by the World Health Organization (WHO) for any new unknown pathogen that may cause disease and potentially an epidemic in the future. Image Credit: Lightspring

What is Disease X?

Disease X is a deadly plague and an outbreak of a flu-like illness, which can result in a pandemic that can kill millions of people worldwide. In 2018, the WHO classified Disease X as more deadly than the Lassa fever and the Ebola virus disease.

Disease X also represents the knowledge that a serious international epidemic could be caused by an unknown pathogen to cause morbidity and mortality. During that time, the diseases being studied by the WHO include the Crimean-Congo hemorrhagic fever (CCHF), Lassa fever, Ebola virus disease, Marburg virus disease, Nipa and henipaviral diseases, Middle East Respiratory Syndrome coronavirus (MERS-Cov), Severe Acute Respiratory Syndrome (SARS), Rift Valley fever (RVF), and the Zika virus.

Coronavirus infection magnitude

The coronavirus disease (COVID-19) is thought to have emerged in late December 2019 in a seafood market in Wuhan City, Hubei Province, China. Since then, the virus has spread to 30 countries across the globe.

As of writing, there are 79,152 confirmed cases of the deadly virus, and it has killed 2,470 people, most of whom in the epicenter of the outbreak in Hubei Province. The majority of the cases were in mainland China, while outside the country, South Korea reported the greatest number of infections, with 763 cases, followed by Italy with 155 cases.

The WHO has declared the coronavirus a global health emergency on Jan. 30 due to the rapid spread of the virus. Many countries have already closed their borders from countries with many confirmed cases.

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South Korea has seen the rapid spread of the disease in the country, prompting officials to declare the highest alert advisory. The number of cases increased from 31 on Feb. 18 to a staggering 763 six days after. The sudden spike in infections can be traced to the city of Daegu. Officials have identified a religious group, the Shincheonji Church of Jesus, as a coronavirus hotbed, where an infected woman attended masses for several occasions.

The virus has spread to 30 countries, including South Korea, Italy, Japan, Singapore, Hong Kong, Iran, Thailand, United States, Taiwan, Australia, Malaysia, Germany, Vietnam, the United Arab Emirates, France, Macau, Canada, the United Kingdom, Philippines, India, Russia, Spain, Lebanon, Nepal, Cambodia, Israel, Belgium, Finland, Sweden, Egypt, and Sri Lanka.

Is the coronavirus the Disease X?

The coronavirus is fast spreading, and if it is not contained, it can become catastrophic. The WHO director-general Tedros Adhanom Ghebreyesus raises concern about the increasing number of the coronavirus without a clear epidemiologic link.

He added that what they fear is if the virus spreads to a country without a sound and strong healthcare system. He fears that if the virus reaches these countries, which have weak healthcare systems, it can be devastating.

Now, scientists caution that the virus’s way of infection is still unclear. During the first weeks of its spread, the incubation period was estimated to be a couple of days to 14 days, but new cases have emerged with longer incubation periods. Further, the disease can be transmitted from human to human, with aerosol and droplets as a possible mode of transmissions.

With several things still unclear about the virus and how it spreads, scientists say that the novel coronavirus fits the disease X category.

“Whether it will be contained or not, this outbreak is rapidly becoming the first true pandemic challenge that fits the disease X category, listed to the WHO’s priority list of diseases for which we need to prepare in our current globalized society,” Marion Koopmans, head of viroscience at Erasmus University Medical Center in Rotterdam, and a member of the WHO’s emergency committee wrote in the journal Cell.

“Time will tell whether the consolidated efforts of the Chinese authorities and the international public health and research community will succeed. But we also need to understand how we make this model of preparedness future-proof,” she added.

Sources:

World Health Organization (WHO). (2018). Prioritizing diseases for research and development in emergency contexts. https://www.who.int/activities/prioritizing-diseases-for-research-and-development-in-emergency-contexts

World Health Organization (WHO). (2020). Coronavirus disease 2019 (COVID-19) Situation Report – 33. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200222-sitrep-33-covid-19.pdf?sfvrsn=c9585c8f_2

Zhang, Y., Koopmans, M., Yuen, K., Andersen, K., Perlman, S., Hogue, B., and Eckerle, I. (2020). The Novel Coronavirus Outbreak: What We Know and What We Don’t. Cell. https://www.cell.com/cell/pdf/S0092-8674(20)30171-9.pdf

The coronavirus may have emerged from a Wuhan laboratory leak, which studies deadly pathogens such as the SARS virus, scientists suggest.

Health officials believe that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), originated from wild animals sold in the Huanan Seafood Wholesale Market in Wuhan City, which is home to 11 million residents.

Now, a team of scientists from Xishuangbanna Tropical Botanical Garden of Chinese Academy of Sciences, South China Agricultural University, and Chinese Institute for Brain Research wrote in a paper published on ChinaXiv, about an alternative source of the coronavirus that is currently spreading across the globe.

The scientists say they have found genomic evidence that the seafood market is not the actual source of the outbreak. Instead, they point the source of the virus outbreak to a laboratory that studies potent viruses.

The Wuhan Virology Institute researches some of the world's most dangerous pathogens. It is China's first Biosafety Level 4 laboratory, the highest security level needed to isolate dangerous biological agents in an enclosed facility.

Image Credit: Connect World / Shutterstock

The spread of the virus

The scientists in the study speculated that the outbreak of the virus has started before December 2019, probably beginning in late November. Further, the busy seafood market may have facilitated the transmission of the virus to buyers, and from buyers to residents across the city.

In the study, the researchers collected genome-wide information from 93 new coronavirus samples shared on the GISAID EpiFlu, which is an international database storing information about the influenza virus. The team studied the evolution and human-to-human transmission of the coronavirus over the past two months.

The samples were taken from 12 countries, wherein 54 came from China before Jan. 22 and the other 39 samples were from France, Australia, Japan, and the United States after Jan. 22.

The team also found that while the virus had spread in the seafood market in Wuhan, there had also been two major population expansions, dated Dec. 8 and Jan. 6. Further, scientists believe that the virus originated outside the market, but the crowded market had boosted the circulation of the coronavirus, spreading it to the whole city by December 2019.

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The first case manifesting symptoms emerged on Dec. 8, and most of the following cases were linked to the seafood market. On Jan. 1, the seafood market was closed, but the virus had already spread in the city, suggesting that the outbreak has started through human-to-human transmission by late November.

Warning about the new virus

“The study concerning whether the Huanan market is the only birthplace of SARS-CoV-2 is of great significance for finding its source and determining the intermediate host to control the epidemic and prevent it from spreading again,” the researchers said.

The researchers also said that while at the beginning of the outbreak in Hubei province and neighboring areas, China’s National Center for Disease Control and Prevention issued a level 2 emergency warning about the new outbreak on Jan. 6, the information was not widely shared. The team said if warning received more attention, the number of cases in China, and across the globe would have been reduced.

The government has locked down Wuhan city on Jan. 23, which is weeks after the outbreak has been reported. Before the residents were barred from leaving the city in fear of spreading the virus, millions have already left.

The Wuhan Institute of Virology, which is the only laboratory in China that is equipped to study with such deadly infectious diseases, released a statement saying that the rumors had caused great harm to the researchers of the laboratory.

The origin of the new coronavirus is still unknown, but scientists and the World Health Organization (WHO) said it is most likely an animal reservoir.

Coronavirus by the numbers

The coronavirus disease (COVID-19) has already spread to 30 countries, with South Korea reporting the greatest number of infections after China. As of writing, there are 763 people in South Korea testing positive for the deadly virus.

The coronavirus has infected nearly 80,000 people, most of whom in mainland China and the death toll has reached 2,670, which is more than twice the number of deaths linked to SARS in 2003.

Countries across the globe, particularly those fearing the rapid spread of the virus, have imposed travel bans from countries who have confirmed cases of the coronavirus. Meanwhile, Italy has also reported a spike in cases, with 155 people testing positive while three patients have succumbed to the disease.

The World Health Organization (WHO) reported that no new countries had reported confirmed cases in the past 24 hours.

Sources:

  • Decoding evolution and transmissions of novel pneumonia coronavirus using the whole genomic data, Yu, Wen-Bin, Tang, Guang-Da, Zhang, Li, Corlett, Richard, http://www.chinaxiv.org/abs/202002.00033
  • World Health Organization (WHO). (2020). Coronavirus disease 2019 (COVID-19) Situation Report – 34. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200223-sitrep-34-covid-19.pdf?sfvrsn=44ff8fd3_2
  • http://www.ecns.cn/news/sci-tech/2020-02-23/detail-ifztvsqr0576579.shtml
  • https://www.globaltimes.cn/content/1180429.shtml
  • https://news.cgtn.com/news/2020-02-23/New-study-shows-Wuhan-seafood-market-not-the-source-of-COVID-19-OjhaHnwdnG/index.html