ImmYOUnology

More than just vaccines


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Norovirus! (AKA the 24 hour stomach bug) Can it be avoided?

The other day I found myself in the break room near my lab eyeing a container of chocolate-covered nuts left over from the Christmas holiday.  Someone left them out as a treat for foraging graduate students and post-docs.  I stood for a moment holding a single piece in my fingers and as I was about to put it into my mouth, I remembered—Norovirus!

I had no reason to think the nuts could be a reservoir of norovirus, but I did have good reason to avoid shared uncooked food with an unknown history.   A good chunk of my family had just had their holiday ruined by the virus, sometimes known as the 24-hour bug or stomach flu.  It causes gastroenteritis, or inflammation of the gut, complete with diarrhea, vomiting and overall exhaustion.  It can only be transmitted via stool or vomit, and though there was certainly none of that visible in the bin of delicious looking nuts, I began to think of all the hands that may have been inside. If it came from a family holiday party, some of those hands may have belonged to kids who haven’t yet learned to wash them for a full 30 seconds after using the bathroom. I threw the candy away, closed the container and left the break room.

I may have avoided norovirus that day by a judicious food choice, but not everyone has that moment of doubt before sharing a drink, holding a child’s hand or ordering a deli sandwich.  It is sometimes just unavoidable, especially because it’s contagious for up to two weeks after the first horrible 24 hours. The center for disease control estimates that 19-21 million people are infected with norovirus each year and it’s actually responsible for somewhere between 600 and 800 deaths per year. Those most vulnerable are either over 65 or under 5 years old.

These figures are driving researchers to search for a vaccine, even if just for those most vulnerable or during outbreaks.  But norovirus, or I should say noroviruses are particularly complicated. They are split into 5 groups (I-V) based on how similar their DNA sequences are. Those groups, called genogroups, are split into anywhere between 8 and 30 genotypes and those can be further divided into variants.  The classification is complicated enough to require the use of a software program that compares genome sequences.

Only three of the genotypes can infect humans and the strain GII.4 has been the most common cause of outbreaks since the early 2000s.  For decades before that, a different strain dominated, and the power structure may shift again.  The abundance of genotypes and variants and their changing frequencies in communities make vaccine design a daunting task.  On top of that, researchers are still discovering new genotypes and variants.  In 2012 a strain called GII.4-Sydney was identified in Australia and made its way to the UK and the US within a year.

Norovirus 4

Up close scanning electron microscopic image of norovirus particles

There is evidence that infection with norovirus can generate immunity in some people, meaning that once they get infected, they are protected from re-infection for some weeks or months. However, no one knows how all of the viral subgroups and variants might affect immunity and vaccine design. In a study published in September, researchers from the University of Florida infected mice with one of two closely related norovirus strains and found major differences in the immune responses.

One of the two strains was much better at activating a class of immune cells called antigen presenting cells. These include dendritic cells and macrophages, and they are experts at displaying pieces of virus and training B and T cells to respond to the infection and turn into memory cells. As a result of the enhanced response, infected mice were protected from a reinfection six weeks later.

{Researchers determine “protection” by measuring how much virus shows up in an animal’s organs after infection. In this case, they measured norovirus in the small and large intestines and in the lymph nodes attached to the intestines.}

Oddly enough, the researchers narrowed down the cause of these changes down to a group of structural proteins whose sequences only varied by about 10% between the two strains.

A key finding in this study was that the protective norovirus strain protected mice from re-infection with both strains.  This is important since any vaccine against norovirus would have to protect against several strains and genotypes. It also points out specific characteristics of the immune response that make all the difference between becoming immune or getting re-infected, for example, robust antigen presentation and B and T cell memory.  A vaccine that could foster those characteristics could potentially protect people from several norovirus strains.  It may take a while to get there. In the meantime I will keep my hands clean and out of community candy dishes.

prevent-norovirus

*A reader noted that the poster above says norovirus is contagious for 2-3 days, whereas I wrote above that it can be contagious for 2 weeks.  To clarify, the virus is most contagious for 2-3 days, but it can continue to be shed in stool for 2 weeks. See http://www.cdc.gov/norovirus/preventing-infection.html for more.

Sources:

The CDC

Zhu S., Regev D., Watanabe M., Hickman D., Moussatche N., Jesus D.M., Kahan S.M., Napthine S., Brierley I. & Hunter R.N. & (2013). Identification of Immune and Viral Correlates of Norovirus Protective Immunity through Comparative Study of Intra-Cluster Norovirus Strains, PLoS Pathogens, 9 (9) e1003592. DOI:

Hoa Tran T.N., Trainor E., Nakagomi T., Cunliffe N.A. & Nakagomi O. (2013). Molecular epidemiology of noroviruses associated with acute sporadic gastroenteritis in children: Global distribution of genogroups, genotypes and GII.4 variants, Journal of Clinical Virology, 56 (3) 269-277. DOI:

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Getting a better a picture of human immunology

Most of our organs stay in place.  The immune system is different. It moves, it migrates, it ebbs and flows.  Our immune systems are made up of free agent cells that can go to almost any organ and release proteins and compounds that kill viruses, bacteria and infected cells.  Some of these free agents live in the spleen or the lymph nodes.  Some just troll around in the blood looking for pathogens or signals and will go back to these organs or die if they can’t find anything interesting.

There are two kinds of cells that can live a lot longer; even throughout your lifetime.  They start out as B cells or T cells. (B cells come from the bone marrow originally and T cells from the developing thymus.) B and T cells adapt themselves to specific parts of invading viruses and bacteria, so they’re called “adaptive immune cells.”  Some become memory cells after this adaptation, meaning they can respond with a vengeance if they see the same pathogen coming around a second time.  This is the basis for vaccination.

Picture1

Memory cells need a place to live.  Some live in the spleen and some B cells go back to their roots in the bone marrow to live out their days in peace.  It’s been thought that memory T cells just float around in the body as rouge patrollers and quickly arrive at an organ whenever a repeat offender like the flu rears its ugly head.  But recently, Donna Farber and her lab at Columbia University reported that those reacting memory T cells found at a site of re-infection had been there since the first infection.  They were residents of the lungs and they were very different from the memory T cells in the blood and spleen.

The idea makes sense. The most effective and well-adapted T cells are ready to meet the offending virus on its turf, in this case the lungs. This work, like much immunology, was done in mice, which raises the question, What does this mean for humans, or for vaccine development?  Scientists know so much about the “where and when” features of immune responses because we can pull out any mouse organ at any time and look for any type of cell.  We can count them, classify them, collect them and inject them into another mouse.  You name it, it can be done.

Human immunology, for obvious reasons, can’t be done this way.  Most work done on human immune cells is done with blood samples.  So if memory T cells in organs are fundamentally different from those in the blood, as Dr. Farber’s work suggests, we really only have half the picture.  And it may not even be a very accurate half.

Dr. Farber saw that if we mean to understand the human immune system, our methods have to change.  She initiated a collaboration with the New York Organ Donor Network and her lab has been able to process fresh samples from otherwise healthy brain-dead donors to study the true distribution of immune cells in the human body. The group initially described T cells in the lungs, intestines, spleens, lymph nodes and blood of 24 donors.  The study wasn’t important because of any complicated experiments or newly discovered drug targets, but because it lays out groundwork that has never before been possible.

Biopsy tissues from sick patients (often people with immune diseases) have been the mainstay for immunologists doing human work. The subjects in this study were mostly healthy because they were cleared to be organ donors. The care taken with the tissues and the speed with which they were processed allowed Farber and her group to do more than look at the tissues under a microscope; they were able to culture them and test their functionality. The arrangement also meant that this was the first time multiple tissues taken from the same donor at the same time could be used for immunology studies.

Dr. Farber’s work is providing physicians and immunologists with a picture of the steady state immune system that has never before been available.  And collaborations with other immunology specialists will address other subsets of immune cells in the same tissues. Recently, her group demonstrated that memory T cells against flu live in specific niches along the airways of human and mouse lungs.

The author of a commentary on Farber’s work brought up a 16th century physician named Vesalius, the first to promote post-mortem dissection in a time when the prevailing knowledge of human anatomy was based solely on animal dissection.  Even as our understanding of the mouse immune system grows and becomes more complex, there is huge value in stepping back and defining the basics of the human immune system.

Teijaro J.R., Turner D., Pham Q., Wherry E.J., Lefrancois L. & Farber D.L. (2011). Cutting Edge: Tissue-Retentive Lung Memory CD4 T Cells Mediate Optimal Protection to Respiratory Virus Infection, The Journal of Immunology, 187 (11) 5510-5514. DOI:

Sathaliyawala T., Kubota M., Yudanin N., Turner D., Camp P., Thome J.C., Bickham K., Lerner H., Goldstein M. & Sykes M. & (2013). Distribution and Compartmentalization of Human Circulating and Tissue-Resident Memory T Cell Subsets, Immunity, 38 (1) 187-197. DOI: