Image post 9: infection blocks trash removal to cause ulcers, cancer

What's that ... a meteor blazing past a molten planet?  No, it's a self-destructing cell just shed from a gastric gland made up of the tightly packed blue cells running across the bottom.

Gastric glands that secrete digestive juices into the stomach, like all epithelial cells (skin, lining of blood vessels, etc.), constantly shed old cells from their outer layers and replace them with new ones. The turnover keeps tissues viable throughout adult life. When the shed cells sense they have outlived their usefulness, they initiate self-destruct mechanisms.

With some cells always in the process of self-destructing, other nearby cells are charged with swallowing up the dying cells and disposing of them. That explains the red cloud surrounding the yellow dot at the center of the image. An antigen-presenting cell (dyed red) has engulfed a self-destructing cell (yellow) to remove it.

The system works pretty well until a person's stomach gets infected with the bacteria Helicobacter pylori.

The infection causes cells to release TNF-alpha, a signaling chemical that triggers the waves of cell activation and chemical release meant to kill invading bacteria or viruses (inflammation). While the process protects us against infectious disease, it also plays a role in many disease processes when it goes too far.

A recent study by a team of UAB researchers found that, along with triggering inflammation, TNF-alpha also blocks the engulfment and removal of dying cells. Cellular debris builds up to drive further inflammation in a vicious cycle.

Why does this matter?  Inflammation caused by Helicobactor pylori is behind the development of nearly all ulcers. Furthermore, the same chronic inflammation damages DNA, creating risk for hard-to-treat gastric cancer.

The image was created by Diane Bimczok, DVM, Ph.D., an instructor in UAB's Division of Gastroenterology and Hepatology, using routine fluorescence microscopy and digital imaging. Phillip Smith, M.D., was senior author of the related study. 

Image post 3: dangerous clumps of fungus

While most posts from The Mix feature a science story, we have also begun sharing images coming out of UAB research. Below is a brief description of what we are looking at and how related work may help to diagnose and treat fungal infections.

Here is a scanning electron microscope image of the fungus called Aspergillus. It's in the process of germinating, or emerging from round spores (at the center) to begin growing. The fungus has sprouted long, branching filaments called hyphae.

Most people breathe in Aspergillus spores daily without incident, but those with lung diseases or weakened immune systems can contract Aspergillosis, symptoms of which range from allergic reactions to severe lung infections. The fungus is a major player in some forms of allergic asthma, as clumps of hard-to-remove hyphae build up in the lungs.

According to the CDC, fungal infections pose an increasing threat to public health because of the growing number of people with weakened immune systems, including AIDS, cancer and transplant patients. In addition, treatment-resistant fungal infections have emerged as a growing problem in hospitals. Global warming may be contributing to an increase in infections, as fungi thrive in warm, moist conditions. Please see the CDC fungal page for more.

Current treatments are largely incapable of reducing morbidity and mortality in Aspergillosis, said John Kearney, Ph.D., professor in the Department of Microbiology within the UAB School of Medicine. He and his team are developing a new kind of vaccine that could provide protection against invasive Aspergillosis. Bacteria elicit a stronger human immune response than fungi but contain some of the same proteins (e.g. chitin). Based on these common building blocks, it may be possible to develop a vaccine where bacterial protein vaccine ingredients are used to activate immune cells that also target a fungus and remove it from the body.

This image was made by Dr. Jeffrey Sides from the Kearney laboratory at UAB using an instrument made available by the UAB School of Engineering.

CMV: we all have it but some babies lose hearing

Most of us are infected with it at some point with no symptoms, but that's little comfort to the babies born with a symptomatic version, some of whom lose their hearing. It's cytomegalo virus or CMV, a common virus that infects people of all ages.

This relative of herpes viruses is mostly a problem for those whose immune systems are weak, including the old, people with HIV and those taking drugs that knock down immune defenses, as well as for fetuses and infants.

A mash up of studies puts the estimated number of babies born each year with a congenital infection between 20,000 and 40,000 (.5 percent of all births). Most children are fine, but a few lose their hearing, and even fewer suffer birth defects or die.

Shannon Ross, M.D., associate professor in the Department of Pediatrics within the UAB School of Medicine, last year won a grant from the National Institute on Deafness and Other Communication Disorders (NIDCD) to try to figure out which traits of which versions of CMV match up with symptoms. She talked with The Mix about how having a marker to tell which babies are most at risk would help researchers decide when treatment with antiviral drugs, which come with serious side effects, is worth it.



Show notes for the podcast:

1:19 Between 20,000 and 40,000 babies in the United States, .5 percent of all those born in a year, are estimated to be infected with CMV.  Many studies have looked at this number, but each was conducted in a small group with its own unique characteristics in terms of mother's average viral level, economic status and region.  So the range is a combination of those estimates.

2:10 Of that 20,000 to 40,000, about ten percent are born showing symptoms of their viral infection, that is obviously ill from it. The babies may have petechiae, small spots on their skin caused by broken blood vessels. They may have an enlarged liver or spleen thanks to the infection, or be relatively small for how long their mothers carried them.

2:45 The field does not know why some babies show symptoms at birth and other don't. One theory holds that it might have to with when the baby was infected during the pregnancy, early or late.

3:13 Of all babies born with congenital CMV, about 10 to 20 percent go suffer for some form of hearing loss, with the risk varying based on whether or not the baby was born symptoms. Of those born with symptoms, perhaps 40-50 percent will have hearing loss. For the majority that are born without symptoms, about 10 percent go on to have hearing loss.

3:57 Dr. Ross recently won an NIDCD grant to study whether or not certain characteristics of the CMV virus can be linked to hearing loss.  In particular, they are examining when any certain strain of the virus, or combination of strains, is more closely associated with hearing loss.

4:35 While the question requires further study, evidence suggest that infected children might have up to five different strains of the virus in one infection. This idea is based on the results of past, small studies, but bigger ones on strain variability are underway.

5:23 Dr. Ross is hoping a strain or combination of strains can be identified as a marker for both whether or not a baby will have any symptoms, and whether or not that child is at risk for hearing loss.

6:06 It may be that a certain gene or version of a gene in a certain viral strain will hold the clue for how CMV causes disease, offering new clues that guide future treatment.

6:42 There has been a lot of interest in screening all babies for the virus because it's a common cause of hearing loss, said Dr. Ross. But for the many children born without symptoms, there is currently no way to determine which is at risk. Physicians don't know which children in the non-symptom group need to be watched closely for an early intervention. They don't know which kids need to get hearing AIDS to preserve their ability to learn to speak

7:48 Complicating matters is the availability of an approved drug for the treatment of CMV called ganciclovir. The problem is that the drug comes with considerable side effects like neutropenia, a loss of white blood cells, so you can't just give it to every infected baby without thinking twice. It becomes a balancing act for doctors between a child's risk for hearing loss versus exposing them to the side effects that could increase their risk for other infections.  For that reason, the field has chosen to treat a subset of babies born with symptoms, but not those born without them. No one will even study the question of whether ganciclovir can preserve hearing in non-symptomatic children, said Dr. Ross, until a marker points to which ten percent of them are at greatest risk.

9:02 Theories for how CMV infection might cause hearing loss include that just the virus making copies of itself may damage the inner ear, or that our body's immune response to the CMV may be the culprit.

10:11 When children lose their hearing from CMV, it can happen at birth or between ages one and two. The latter, delayed onset hearing loss happens when children are learning to talk, and has an additional cost in terms of learning and developmental delays.

11:15 Unlike HIV for instance, there is no good animal model for the study of CMV. There are many animal versions of the virus, but they do not react to CMV like human cells do. Plus, the animal versions do not cause congenital infections like they do in humans. That has made it very hard to understand the basic mechanisms of the disease (e.g. how the virus reproduces or infects cells).

12:13 Dr. Ross and colleagues are now doing "deep sequencing" of the genes in each strain of CMV virus taken from blood or urine of babies with congenital CMV infection.  They can then examine the entire gene code of each "quasi-species" (strain) of virus looking for genetic variations between strains that may contribute to the presence of symptoms. The team is now sifting through large amounts of data looking for patterns that could establish a marker.