Monday, March 23, 2020

Mosquito salivary gland protein

Mosquito-transmitted viruses have evolved ways to enter and persist in human populations. Evidence has shown that mosquito salivary gland proteins can manipulate host cellular and immune responses in a manner that enhance viral transmission efficiency from mosquitoes to humans, an essential step in the lifecycle of flaviviruses.

This study focused on AaVA-1, an Aedes aegypti salivary protein, which promotes flaviviral replication in human monocyte-lineage immune cells, a primary intradermal target of flaviviruses during mosquito bite. Adding AaVA-1 to DENV or ZIKV results in high viremia and disease onset, while removal of AaVA-1 promotes low viral load. Not only does AaVA-1 play a role in transmission  efficacy, it also was found to be a positive regulator of autophagy, a cellular process that flaviviruses have usurped to promote viral replication in host cells.


Novel antiviral targets host nuclear transportin  α/β1 heterodimer

Currently, Dengue virus is treated primarily symptomatically, and, while there is a vaccine, it is not recommended for all people nor is it licensed in many countries. Thus, antivirals are still being investigated and could play a major role in treating this virus whose geography has expanded in recent years.

According to this study, GW5074 has potential as an anti-viral for flaviviruses. The mechanism of inhibition involves limiting NS5 nuclear targeting by halting NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Inhibitors able to prevent nuclear import of viral proteins like NS5 are promising for anti-DENV treatment. The role of NS5 protein seems to be to suppress host antiviral response, partly through impacting host mRNA splicing. Thus, establishing that GW5074 has strong antiviral activity against DENV-2 as well as other flaviviruses, ZIKV and WNV, confirms that NS5 nuclear localization is a viable target for antiviral therapies.

- Micah

Tuesday, March 17, 2020

Aspirin able to reduce liver cancer risk?

Hepatocellular carcinoma is the fourth-leading cause of cancer mortality worldwide. This cancer primarily is driven by infection with viral Hepatitis B and C. While many cancers are declining in incidence, HCC is not.

A nationwide observational study based in Sweden identified low-dose aspirin as reducing risk of liver cancer and liver-related death in individuals with viral hepatitis. Though it is too early in studies to begin regularly prescribing low dose aspirin to all patients with viral hepatitis, the results of this particular study are promising. This study confirms a duration-response relationship with low-dose aspirin.  One next step would be a study with randomized participants in order to gather prospective data.

- Micah

Tuesday, March 10, 2020

Some good news: China appears to be getting the upper hand

While the news around the globe surrounding the spread of the Covid-19 virus continues to be bleak, with outbreaks and deaths in new places almost every day, the tide seems to have turned in China where it all started.   According to an Associated Press dispatch , China reported just 119 new diagnoses on Tuesday, March 4. That number is significantly below the diagnosis rate just 10 days earlier and marks a major shift in the virus’s momentum within China.   In addition, China, which has both the bulk of the world’s infections (more than 80,000) and 95% of the reported deaths caused by the virus, announced that more than 50,000 people have fully recovered from illness associated with the virus and the city of Wuhan, ground zero for the spread of the virus, closed the last of its emergency hospitals and discharged its final patients.    While these early week reports of diminishing infection rates encouraged observers to believe that the virus had largely run its course in China, China’s infection rate ticked up in a real but statistically insignificant way by the end of the week.   Notwithstanding the minor variation in reported infections, experts still believe that the worst if over in China.

Meanwhile, the West is bracing for the epidemic with equal measures of panic and fear.   The U.S. reported more than 230 active cases by weeks’ end, with major universities including Stanford, NYU and three in the Seattle area , announcing that they would suspend classroom and other meetings for the foreseeable future to try to inhibit further infection.  As detailed in countless news and online reports and dramatically reflected in the U.S. and other stock markets, the impact of the virus’ spread—and even more so, the fear of the virus’ spread— on the world’s economies has been extraordinary.

~~ David M. Walsh

Hinnant, L. And Moritsugu, K., “Virus crisis ebbs in China, spreads fear across the West.”  Associated Press.  (Paris) March 3, 2020.  Republished in the Marin Journal, March 4, 2020.

Evolution of Coronavirus, seen from Wuhan

Last week, on March 3, 2020, an article (accepted manuscript) was published in the National Science Review. The article, titled “On the Origin and Continuing Evolution of SARS-CoV-2”, was authored by scientists from Peking University, Chinese Academy of Sciences, Peking Union Medical Collage, and Shanghai University. The authors discussed their findings of a single nucleotide mutation of the SARS-CoV-2 in the early days of the epidemic, or single nucleotide polymorphism (SNP). According to the authors, this new mutated type, given the name L-Type, is more “aggressive” than the ancestral S-Type. While L-Type is sending more people to the hospitals, the S-Type is one that is spreading more widely. Hence the apparent larger number of people with milder cases of Covid-19. (1) [NOTE: for a summary of the findings, see Coronavirus Epidemic Update 31, 2:21]

Another scientist, in his response to the article by the Chinese scientists, pointed out that when an RNA virus changes hosts, mutation often happens because the virus needs to adopt to the new host. In the case of SARS-CoV-2, that new host is us! (2)

Back in 2004, when the first SARS were happening, scientists already wrote about the viral evolution of coronavirus, and noted that among the emerging viruses, majority are RNA rather than DNA viruses. RNA’s higher mutation rate is one reason why RNA viruses adopt better to new hosts than DNA viruses, and accounts for its agility to cross species. (3)

Looping back to my first blog on the Global Virome Project, it is more apparent now than ever the need to invest in the project to map the viruses in the animal kingdom and other kingdoms, such as the marine viruses, to gain data and knowledge in the understanding of future emerging viral diseases.

~~ You Jia Zhu

1. Xiaolu Tang, Changcheng Wu, Xiang Li, Yuhe Song, Xinmin Yao, Xinkai Wu, Yuange Duan, Hong Zhang, Yirong Wang, Zhaohui Qian, Jie Cui, and Jian Lu, “On the origin and continuing evolution of SARS-CoV-2”, National Science Review, March 3, 2020.

2. “Expert Reaction to Study Looking at Whether There Are Two Strains of the Novel Coronavirus”, Science Media Center, March 4, 2020.

3. Edward C. Holmes and Andrew Rambaut, “Viral Evolution and the Emergence of SARS Coronavirus”, The Royal Society, July 29, 2004.

The ‘London Patient'

Apoorva Mandavilli’s article titled, The ‘London Patient,’ Cured of H.I.V., reveals that Adam Castillejo formerly known as the “London Patient” to protect his identity is just the second person in the world to ever be cured of the Human Immunodeficiency Virus. Mr. Castillejo battled HIV for ten years and recently underwent a bone marrow transplant to help treat his lymphoma cancer, which was a result of HIV. This transplant cured his HIV because the donor “carried a mutation that impeded the ability of HIV to enter cells, so the transplant essentially replaced Mr. Castillejo’s immune system with on resistant to the virus.” Bone marrow transplants is “not a practical option for curing HIV” because the procedure is extremely risky. Mr. Castollejo was diagnosed with HIV in 2003 and immediately adapted a healthy lifestyle regarding exercising and eating better.  But in 2011 he was diagnosed with Stage 4 Lymphoma and underwent chemotherapy, which also made complicated his treatment (medications) for HIV more difficult. In the spring of 2015, doctors revealed that Mr. Castillejo would live to see Christmas. Fortunately, Mr. Castillejo found one of the few hospitals who agreed to perform a “last ditch effort” of a bone marrow transplant with a patient who has HIV. As of today, Mr. Castillejo’s body shows no signs of the virus.

This article relates directly to our “Virus in the News” class because it focuses on the Human Immunodeficiency Virus that we have covered in class through lectures and two presentations involving the virus. After learning more about viruses and specifically the havoc HIV wrecks on the immune system it makes sense that the bone marrow transplant worked. By essentially “giving” Mr. Castillejo a new immune system that blocked HIV from entering the cells the virus was defeated. I do have a question for the class, why is a bone marrow transplant extremely? The article did not elaborate on this subject.

~~ John Sikora

Why is the coronavirus mysteriously sparing kids and killing the elderly?

Why is it that COVID-19 manifests itself so drastically different between young children vs. the elderly? In China, 2.4 percent of reported cases were children and of these, 0.2 percent were chronically ill. In contrast, the fatality rate for those over 80 in China is particularly deadly, estimated at 21.9 percent, according to the WHO, based on over 44,000 confirmed cases. Moreover, fatalities and severe symptoms for children under the age of 10 are almost nonexistent.

The previous coronavirus outbreak, SARS in 2002 killed 774 people, but also spared the young. No children died from SARS in 2002. Similarly, few children developed symptoms from MERS coronavirus which has counted 858 fatalities since 2012.

A virologist from the University of Texas, Vineet Menachery stated that respiratory infections typically show a U-shaped curve with children on one end and older adults on the other, as the immunity of the former group isn’t fully developed and that of the latter group is weakened. However, the U-shaped curve does not apply to COVID-19.

While numerous questions have been explored as an explanation, research to date remains inconclusive. Frank Esper, a pediatric infectious disease specialist at Cleveland Children’s Clinic suggests the possibility that the answer may have “nothing to do with the virus and has to do with the host, like underlying conditions in the lungs, diabetes, or hypertension.”

Menachery and his lab have conducted experiments with mice, finding that baby mice ward off coronavirus infection, while the lungs of older mice become ravaged from the disease. Moreover, Menachery found that the cause of the older mice’s fatalities were related not only to compromised immune systems, but a “disregulation’ that caused their immune systems to overreact to the SARS coronavirus. That’s similar to how humans die of infections from (COVID-19).”

Interestingly, Esper ads, “I suspect there’s something more mechanical than immunological going on…Something about the receptors in children’s bodies or their lungs is interfering with the virus’ ability to attach itself.” This comment from Esper is particularly relevant to my recent research of the coronavirus and the relationship between the spike protein trimers and the host receptors of ACE2 located deep in the bronchii.

The article also states that while children show much milder symptoms of COVID-19, contact testing—testing people who come in contact with a confirmed case—shows that children are getting infected at similar rates as adults. Thus, children are potential drivers of infection, spreading the virus to parents, relatives, and the wider community. For this reason, closing schools could help protect adults and staff from the outbreak.

~~ Janette Canare