Monday, December 15, 2014

Johan Hultin

Remember him? He’s the pathologist who discovered tissues containing the 1918 influenza virus, which allowed the virus to be sequenced for the first time. Bob talked about him a bit in class, but Johan Hultin’s story is so darn cool I thought I’d look into it a little bit more.

Hultin was taking a break from Swedish medical school and studying microbiology at the University of Iowa and a professor happened to make a passing remark that intact samples from the 1918 flu still exited in frozen in bodies in the Artic. Hultin was looking for a dissertation topic and proposed that he try to find the virus so it could be used to make a vaccine. (I’m not sure the logic of trying to use an old strain to make a vaccine against a new strain, but maybe this was before some newfangled techniques and it was the best they could do.)

In any case, in native groups in the Alaska, death rates from this outbreak virtually wiped out small villages. Johan Hultin’s enthusiasm was probably fueled by the fact that he spent a summer in Alaska with a paleontologist and believed that driving up the newly opened Alaska Highway, “was itself a great adventure.”

 In order to establish where the mass graves were, he wrote to a few missionaries. They sent him copies of record books in Norwegian. Being Swedish, he luckily happened to be able to read Norwegian.

Off Johan went to Alaska, to a village now called Brevig Mission, to be specific. The villagers let him excavate. Once he got the samples, he had to quickly get them into the lab. A storm made the bay almost impassable and dry ice brought to refrigerate the samples had evaporated. Johan and his small team used carbon dioxide from a fire extinguisher to make dry ice and with local help, they managed to find an overland route.

Despite this extraordinary effort, Johan’s first attempt was unsuccessful. He concluded that there was no live virus in the corpses. He planned to write about the failed attempt for his thesis, but he was accepted into the medical school at the University of Iowa and never ended up writing it.

It turns out that the Army was also trying to get the Spanish flu out of the ice, but found only skeletons in their original excavation site. Tauenberger, the civilian scientists who heads the microbiology division of the Armed Forces Institute of Pathology, wondered whether it’d be possible to get the Spanish flu out.  He was able piece together a gene called NS from 78 soldiers and published a report. Hultin happened to read the report and offered to bring Tauenberger frozen samples from Alaska with the flu.

Hultin returned to Brevig Mission. The local people were worried about releasing bad spirits and were relucantat to allow him to dig. Eventually, someone recalled that they had been given Christian burials, which was supposed to have sufficiently driven the bad spirits away, so they gave Hultin the go ahead.

Hultin and his crew found a body he had missed the first time, a fat woman in her thirties. The fat apparently helped insulate her body from the brief thaws. In fact, the material that Hultin brought back was more fragmented than the Tauenberger’s soldiers. However, Hultin gave him all the material he needed and the virus was sequenced 8 years later.





















References:

Epidemiology meets evolutionary ecology

I read an article titled “Epidemiology meets evolutionary ecology” a few weeks ago, but have not had a chance to fully digest it. I think it’s potentially useful to think about viruses this way so I’m going to write down a few points that I find interesting.  Probably the most important point that this paper makes is the definition of virulence, or “the extent of parasite-induced reduction in host fitness.” (Although it still seems odd to me that virulence is defined based on the host rather than the parasite itself....)

1. Optimal Virulence
-Viruses face a tradeoff between host survival and fecundity. Hosts face a tradeoff between the cost of resistance and the risk of infection.

-Estimates of R0 generally do not take into account vertical transmission or multiple infections.

2. Transmission Patterns
-Vertical transmission tends to reduce virulence compared to horizontal transmission because vertical transmission depends on host survival and reproduction. But vertical transmission and horizontal transmission are usually related so it’s difficult to consider these transmission patterns individually. 

3. Spatial structuring of disease transmission and dispersal mechanism
-Recent models that include spatial structuring tend to predict lower virulence than those that don’t.

4. Host heterogeneity
-A host parasite that is optimally adapted to get around one host’s immune system and not another, host heterogeneity selects for lower virulence.
-The relationship between parasite virulence and host resistance is more complex than was originally assumed.

5. Competition strains and within-host dynamics
-Viral strains in the same host are competing to a limited amount of resources, which leads to selection for greater virulence.
-Kin selection between related strains within one host is predicted to reduce virulence.

6. Phylogenetic analysis
-Phylogenetic analysis is useful in providing information about emerging strains

7. Public Health Policy
-Evolutionary ecology should be taken into account when implementing public health interventions.

8. Sex and Virulence
-It is thought that sex in parasites increases virulence and sex in hosts reduces virulence.

Phew! That just made my brain hurt a little bit more. And I just discovered that there’s a great table in this article, which distills down the major points better than I just did. (There’s a screen shot below, but you should check out the original!) Also, the author makes the point that “the misconception that parasites will ultimately evolve towards avirulence has only been dispelled gradually from the medical literature.” (Proof of these “misconceptions” prevalence can be found in the abstract of the paper that Emi sent out on HIV.)

By Olivia

References:
Galvani, A. “Epidemiology meets evolutionary ecology.” Trends in Ecology and Evolution Mar. 2003. Vol. 18(3): 132-139.

Sunday, December 14, 2014

Prions in the strangest of places

I was doing some research on Huntington’s disease when I came across the idea that prions, infectious proteins, may be more common than we previously thought. As we all know, prions are accepted as the disease-causing agent in transmissible spongiform encephalopathies, such as Creutzfeldt-Jakob disease.  These infectious proteins form aggregates, and the breakage of the aggregates represents protein replication.

Amyloid plaques, seen in a variety of neurodegenerative diseases, are also are created by the misfolding and aggregation of proteins. Studies on Alzheimer’s and Parkinson’s disease have given some researchers reason to suspect that the proteins involved in these diseases may exhibit prion-like behavior. Apparently an early study on Alzheimer’s found that the disease was transmissible from the white blood cells of people to hamsters. However, this finding was never reproduced. Another study found that aggregates of AB peptide from brains of Alzheimer’s patients could be passed to mice genetically engineered to produce large amounts of the AB precursor protein. Another study grafted health brain tissue into the brains of Parkinson’s patients, and the tissue acquired protein aggregates associated with the disease pathology. Amyloid A amyloidosis can be excreted in feces, and at least in geese, it can induce amyloidosis if ingested.


The author of the 2005 paper published in Nature voicing this idea makes an important distinction between prions and what he calls “prionoids.” Prions are transmissible through populations and can cause epidemics, but “prionoids” can only affect neighboring molecules or cells.  This seems like a very significant distinction to me, and if this is the case, calling the proteins in these neurodegenerative diseases prions seems downright confusing.  However, it’s a very interesting idea and once again blurs the distinction of what we consider life.

By Olivia

 References:
Aguzzi, Adriano. “Cell biology: Beyond the prion principle.” Nature 18 Jun. 2009; 459:924-925.

Herpes and your telomeres

What’s the secret behind that cold sore that pops up on your face at the most stressful of times?  According to a soon-to-be published study by a group of researchers at the Wistar Institute, Herpes Simplex Virus 1 manipulates telomeres, the protective tips of chromosomes. HSV-1 causes the cell to transcribe telomere repeat-containing RNA. The virus then degrades a telomere protein called TPP1, which is involved a protein complex that helps protect telomeres. By disabling this protection, HSV-1 is able to replicate more efficiently. The virus also uses a replication protein, ICP8, which helps promote viral genomic replication.

HSV-1 is not the first herpes virus to manipulate its host’s genome. A review published in the Annual Review of Virology (2014) states that telomeric repeats have also been described for HHV-6, HHV-7, and several other members of Herpesviridae. This new finding for Herpes Simplex 1 is of particular interest because according to the CDC, the virus infects 776,00 new Americans every year.

As a side note, I noticed that the press release for this new study was published well in advance of the December 24th edition of the journal Cell Reports. Is having a press release first normal?   

By Olivia

References:


Osterrieder, N., Wallaschek N., and Benedikt B. Kaufer. “Herpesvirus Genome Integration into Telomeric Repeats of Host Cell Chromosomes.” Annual Review of Virology 2014. 1:215-35.

HIV becoming less virulent

I read the article that Emi sent along about decreasing HIV virulence. In HIV infections the HIV virus faces a tradeoff between high virulence (increasing the likelihood of transmission), and reduced lifespan of the host (decreasing the likelihood of transmission). This study looked at the HLA molecules in Botswana and South African populations and used models to assess ART’s ability to accelerate the effects of HLA-mediated viral adaptation.

HLA genes are an important factor in immune control of HIV-1 infection, as they direct cytotoxic T lymphocytes against virus-infected cells. HIV can only evade this immune response by selecting for mutants that reduce the viral replicative capacity.  The authors also hypothesized that increasing the use of ART would likely remove viruses with the highest replicative capacity from the population, and also lead to a decrease in virulence overtime.

The study examined two populations of ART-naive antenatal mothers in Botswana and another in South Africa. They tested the adaptation of all HIV sequences in the populations against each individuals HLA molecules. To assess whether the frequency of cytotoxic T lymphocyte mutants would increase over a decade, the researchers looked at a second cohort enrolled ten years later at the same site in South Africa.  The authors also created a mathematical model to assess the effects of ART.

This study suggests that even within a decade, the population-wide effects of HIV evolution are evident. The findings show that there is a lack of HLA-B*57 associated protective effect in the Botswana population. This suggests that HLA B and HLA-B*57 are important drivers in the HIV selection, with predictable losses in immune protection. Consistent with the author’s hypothesis, they found a lower viral replicative capacity in the Botswana population compared to the South African population. Although there was an increase in the number of HLA-B*57 mutants in the Botswana subset for which viral replicative capacity measurements were taken, the number of these mutants did not correlate significantly with the viral replicative capacity, which suggests that additional factors are in play.

The authors believe that one factor is the increased diversity of HLA-associated mutations in the Botswana population compared to the South African population.
Another factor to consider is the effect of ART. The study hypothesizes that giving ART to people with low CD4 counts tends to accelerate the evolution of variants with lower viral replicative capacity. The authors’ model suggests increased use of ART also aids in lowering the virulence of HIV. 

The study’s findings have important implications and extrapolated to an individual level, it may mean that more people’s immune system will be able to control disease for longer. If scientists can understand what is required to control the virus, it may help with development of better antivirals or a vaccine. In the very long run, this could help us eradicate the infection.

Remaining questions include what made the North American population that demonstrated a contrary finding to this study different from the Botswana and South African populations these researchers studied? Are these two populations in Botswana and South Africa representative of what is happening worldwide? The authors state, “epidemics in new hosts diminish in virulence over time?” Is this true for other epidemics?  

Thanks to Emi for passing this article on and for an interesting read!

By Olivia

References:
Payne, Rebecca et al. “Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.” PNAS Early Ed., received for review July 15, 2014, approved Oct. 31, 2014.