Journal Club: Virology, Developmental Biology, Immunology, Public Health, and Cancer Biology

Graduate Division

VIROLOGY: Lipid droplet-binding protein TIP47 regulates Hepatitis C virus RNA replication through interaction with the viral NS5A protein. Vogt, D.Aet al. (Ott). PLoS Pathogens. 9(4):e1003302.

Hepatitis C is a single-stranded, enveloped RNA virus that infects mainly hepatocytes. Acute infection with hepatitis C is often asymptomatic, but over a period of years, the virus causes liver-scarring, cirrhosis and even liver carcinomas. During its replication in a hepatocyte, the virus assembles its different proteins and components by recruiting lipid droplets to the endoplasmic reticulum to promote proper viral production. Interestingly, the reason why lipid droplet recruitment is necessary for viral production is poorly understood.

In this paper, researchers sought to identify proteins that link viral assembly via the viral protein NS5A to lipid droplets, by performing a yeast two-hybrid screen for binding partners of NS5A. The host cell’s lipid droplet-binding protein TIP47 was found in this screen and verified by additional protein binding tests.

Additionally, when they knocked down TIP47 expression in host hepatocytes, viral replication was severely diminished. The authors conclude that TIP47 assists viral assembly by helping to integrate lipid droplets where viruses are being made.

DEVELOPMENTAL BIOLOGY: Specialized filopodia direct long-range transport of SHH during vertebrate tissue patterning. Sanders, T.A.; Llagostera, E.; Barna, MNature.  April 28. [Epub ahead of print]

How do you get a cellular signal across long distances within tissues? Most people will think of neurons—which is correct, but is only one method of getting a signal from one cell to another quite far away. During development, when long-range cellular signals are crucial for proper body formation, how do tissues promote the migration of protein signals from cell to cell when those cells are tightly packed together and blood vessels haven’t formed?

In this paper, researchers used sonic hedgehog (SHH) as an example of a signaling protein crucial for proper limb development, to probe how signals move across newly developing tissues.

Surprisingly, the researchers found that after the protein is made, SHH is retained on the cell surface in a particulate form that clusters on an extremely long cell projection called a filopodia. Filopodia were several cell-bodies in length and traversed relatively long distances compared to other cellular projection. This way, developmental signals are spread along tissues in the body over long distances without having to travel to circulation or be transmitted by neurons.

IMMUNOLOGY: Deficiency in IL-17-committed Vγ4+ γδ T cells in a spontaneous Sox13-mutant CD45.1+ congenic mouse substrain provides protection from dermatitis. Gray, E.E. et al. (Cyster)Nature Immunology. April 28. [Epub ahead of print]

When most of us think of the unique underlying characteristic that makes a T-cell a T-cell, we think of the alpha-beta T-cell receptor, or αβTCR. The αβTCR is what makes an individual T-cell specific for a certain protein antigen—each αβTCR is different, which is what allows our adaptive immune system to have such a broad repertoire of protective immunity.

However, there are also delta-gamma, or δγTCRs, that use different gene segments to make a T-cell receptor but that also confer specificity to unique antigens, especially those encountered in the gut. These δγ T-cells are typically found in the gut mucosa, but there is also a subset of δγ T-cells found in the skin. Some of these δγ T-cells become Th17-skewed, which means that they secrete the cytokine IL-17, which tends to be quite inflammatory.

In this paper, scientists found that a commonly used strain of CD45.1+ mice have a spontaneous mutation in the transcription factor Sox13 that results in a defect in skin-homing Th17- δγ T-cells. In a mouse model of psoriatic dermatitis, these CD45.1+ mice had much less skin inflammation because of their lack of skin-resident δγ T-cells.

PUBLIC HEALTH: Social determinants of health and seasonal influenza vaccination in adults >=65 years: A systematic review of qualitative and quantitative data. Nagata, J.M. et al. (Franco-Paredes). BMC Public Health. 13(1):388.

Getting vaccinated every year for influenza is the best way to prevent the flu — and for vulnerable populations such as the immunocompromised, the young and the elderly, getting vaccinated is especially crucial to staying healthy. Unfortunately, despite overwhelming evidence that vaccination helps prevent disease, many elderly individuals do not get vaccinated, and the reasons why are poorly understood.

In this paper, researchers comprehensively reviewed the literature concerning social determinants of elderly vaccination to try to identify the underlying reasons why some populations do not get vaccinated. By analyzing data from 58 published studies, they determined that there was a combination of social determinants, including ones that were structural (such as age, education, ethnicity, etc.) and intermediary (such as behavioral beliefs, perceived susceptibility to flu, etc.) that affected vaccination rates. They identified health care-related factors such as affordability, accessibility and physician’s advice.

CANCER BIOLOGY: Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation. von Figura, G.; Morris, J.P. IVWright, C.V.; Hebrok, MGut. May 3. [Epub ahead of print]

KRAS is a potent signaling molecule that helps to regulate cell cycle and replication; when mutated, aberrant KRAS activity can either result in death of the cell or in dysregulated overgrowth—also known as cancer. In fact, KRAS mutations have been found in multiple types of cancers, including leukemias, colon cancers, lung cancers and pancreatic cancers. Unfortunately, positivity for a KRAS mutation is a contraindicator for a number of normally potent new anti-cancer drugs, making treatment complicated.

In this paper, researchers investigated the role of Nr5A2, a protein that usually helps maintain pancreatic cell differentiation, in the development of pancreatic cancer. They found that even with KRAS mutations, Nr5a2 helps to maintain the differentiation of the cell, thereby limiting the potential for cancer to develop. Nr5a2 mutations, however, abolish this protection, indicating that Nr5a2 is an important susceptibility gene for pancreatic cancer.