Synergism in action: co-infection of a yeast and a bacterium

C. albicans (pink) in murine kidney. Image copyright D. Singleton, YCP

An article in the latest issue of Infection and Immunity caught my attention: “Candida albicans-Staphylococcus aureus Polymicrobial Peritonitis Modulates Host Innate Immunity” describes work by researchers at the Louisiana State University Health Science Center. Many models of infectious disease use virulence studies in animals such as mice. A typical experiment may infect an animal with a defined number of pathogenic organisms, and changes in health of the animal are measured–this is the basic premise of Koch’s Postulates, where the etiologic agent of a disease can be experimentally determined. Some diseases of humans may not be well mimicked in animal models, and this presents a problem when trying to study significant human diseases.

The work summarized here examined the disease produced by two separate pathogens, the Gram positive bacterium Staphylococcus aureus, and the fungus Candida albicans. Infection of mice with either one of these pathogens was non lethal at the infectious doses used in their experiments. However, when an animal was co-infected with both the bacterium and the fungus at the same time and at the same individual dose, a 40% mortality rate was observed, with significant infiltration of the organisms into the peritoneum and other target organs. At the same time, a number of important immune system signalling hormones were also elevated in mice who were co-infected with both pathogens, leading to a much higher inflammatory response in those animals. Mice treated at the same time with the inflammation inhibitor indomethacin did not die. Further injection of mice with a second inflammatory medidator prostaglandin E2 at the same time as administering indomethacin overrode the protective effects of indomethacin, and significant mortality of mice was again observed. The authors conclude that combination of pathogens have very important effects on the innate immune response, and that the lethality of the disease is exacerbated by the powerful inflammatory response.

Nosocomial infections are a critical issue in US health care, with billions of dollars annually being adding to the total costs of our health care. The graphic to the left from our textbook illustrates the relative contributions of various classes of pathogens; the sections of the pie labeled “Gram-positive bacteria” and “Yeast” are comprised primarily of the two species in this report, S. aureus and C. albicans. Many of the organisms responsible for causing nosocomial infections do so due to the a perfect storm of conditions in health care–a population very susceptible individuals, healthy carriers moving between patients, use of antibiotics leading to resistance, medical procedures which can bypass normal routes of entry for these pathogens. The first inclination upon developing a nosocomial infection is to combat it with antibiotics, and in fact many surgical procedures may involve the prophylactic use of antibiotics to help avoid this outcome. But the use of antibiotics themselves can lead to problems in the form of rampant antibiotic resistance and loss of efficacy of those drugs. This research shows that an alternative approach that tweaks the host’s immune response might also be effective.

Fear as an agent of good?

The graph shows the annual number of cases of various cancers worldwide. The fraction of cancers estimated to be induced by HPV is shown in red. For example, nearly all cases of cervical cancer are believed to be caused by HPV. Parkin, D. M. (2006) (Photo credit: Wikipedia)

Our recent discussion about viruses and cancer led Afolake Ogunfuwa (3 PM Micro) to find this summary about the Human Papilloma Virus vaccine:

The  Science daily news website published a discussion about a study carried out by researchers in Ohio State University on the Human Papilloma Virus (HPV) vaccine. The study seemed to suggest that researchers concluded that a promotion of HPV vaccine use, based on scaring the population about cancer may not be working. They maintained that emphasizing the fact that the vaccine prevents a Sexually transmitted disease (STD) may be the way to go.

The website suggested that there is a conventional wisdom that: getting women vaccinated by scarring them is the best way to get them vaccinated. They further mentioned that the “cancer-threat” message has failed and attributed that statement to a lead author of the study on the HPV vaccine, an assistant professor of communication by the name of Janice Krieger. Apparently, the study maintained that women don’t respond to cancer threat, and that young women seemed more worried about getting an STD.      The website discussion went on to briefly describe the study and the driving idea behind it. The conclusion of the study apparently was that putting emphasis on the HPV vaccine ability to prevent genital warts was a clear winner with young women.

Outbreak of a novel avian influenza

Cases and deaths due to H7N9, China–February through April 2013

Here’s a special treat for all BIO230 students; due to a lapse in bonus submissions, I have at least temporarily regained control of the class blog. Alert BIO230 correspondent Heather G has requested an update on H7N9 influenza, a novel influenza isolate that epidemiologists worried, because of its lethality and its potential for further spread.

In late March 2013, the Chinese Centers for Disease Control reported laboratory confirmation of 3 cases of human infection due to an avian influenza, which was determined to be of the H7N9 variety, which had previously never been documented to cause infection in humans. The US Centers for Disease Control and Prevention published a summary of the outbreak this week in the Morbidity and Mortality Weekly Report. As of the end of April 2013, Chinese authorities had confirmed 126 cases of human infection in 8 eastern Chinese provinces, with a fatality rate of 19%. All cases to date appear to be sporadic and of environmental origin, as no obvious human to human contact has been demonstrated outside of 3 family clusters. The origin of the human cases remains under investigation, but is presumed to be due to exposure to live poultry such as chickens or ducks. Of the positive cases for which a complete patient history was available, approximately 75% of the patients has an underlying medical issue which may help to explain their susceptibility to the virus. The US CDC has requested domestic medical laboratories to be on increased surveillance to the disease, particularly with individuals who may have recently returned from this area of China.

Which influenza can kill you (as of today)

Chinese laboratories have already sequenced the genome of this H7N9 isolate, and determined that all of the genes of the virus are of avian origin as opposed to being derived from genetic recombination between avian and mammalian viruses. The viral genome does contain several mutations which increase the ability of this virus to bind to and infect mammalian respiratory epithelial cells, and therefore contribute to the increased virulence of this isolate. Further analysis of this H7N9 variety indicate the presence of resistance genes to the adamantanes, which are a class of important antiviral medications. Consequently, this class of antiviral medications would not be indicated to treat this outbreak.

Chinese authorities are expanding surveillance into potential animal reservoirs with widespread laboratory screening in bird and mammal populations. So far 68,000 bird samples have been screened with 46 positive results. At the same time, 4500 swine samples were examined with no positive results. This suggests that within environmental reservoirs that the virus is being restricted to avian populations. The US government does not allow the importation of live birds, poultry, or eggs from regions with an active highly pathogenic outbreak, and are working to deploy screening procedures to assess whether wild bird populations might be able to import Eurasian influenzas into North American populations.

Editorial notes by the CDC report stress the worrisome nature of this outbreak, primarily because of the speed with which it arose, and because this is the first documented infection of an influenza variety previously believed to be restricted to birds. The CDC recommends that domestic clinical laboratories have plans in place to identify cases here should they arise, and to consider H7N9 infection in patients who have recently returned from areas where the outbreak is continuing. At present, authorities do not feel that travel to China should be restricted, however travelers should practice hand hygiene and safe food practices. Travelers should seek medical treatment for any upper respiratory-associated disease during or after return from travel.

Fatal Flu

Allison Shike (3 PM Micro) found this news alert via Innovations Report. Here is Allison’s summary about influenza and a bacterial infection that was just covered in class:

Scientist from Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna have performed a study on the effects on the lungs of patients with the flu and a bacterial infection. A fatal combination is formed when a flu patient also becomes infected with a bacterial infection. They hope the results will improve patient outcome and prevent permanent lung damage by developing alternative treatments for flu-related bacterial infections.

The flu is caused by an infection of the influenza virus. The virus mainly targets the respiratory tract. Around five to fifteen percent of the population is diagnosed with an upper respiratory tract infection caused by the flu virus. Many deaths also occur of the illness every year. The flu virus and a secondary infection with bacteria mainly cause these deaths.

Influenza increases the susceptibility to a bacterial infection. Legionella pneumophila can normally be fought off by the immune system. During the times of a flu virus Legionella can cause a ling damaging or even fatal type of pneumonia. The scientist thought that the infection was so fatal because the bacteria was growing and spreading like crazy. Further testing showed that the number of bacteria was not altered.

Lung damage caused by the Legionella co-infection will not be repaired properly as the virus suppresses the body’s repairing tissue damage ability. Drugs that activate tissue repair pathways greatly improved the infected patient’s outcome. More options for treatment will be explored to deal with co-infections of the flu and bacteria.

Medicine without antibiotics

Io9.com continues to be my favorite site for science related news alerts, plus spoiler containing updates for Doctor Who and Game of Thrones. A very nice summary of what medicine might look like in the near future was published today, as we enter the “post-antibiotic era.” BIO230 students have often been treated to my dire warnings about how we will increasingly be faced with patients who do not respond to standards of treatment for infectious diseases. The article states that antibiotic resistant infections currently add about $30 billion dollars to US health care costs annually, and this figure is expected to continue to increase. As cited in the Guardian, medical conditions that we can expect drastic changes in the very near future include:

• Transplant surgery becomes virtually impossible. Organ recipients have to take immune-suppressing drugs for life to stop rejection of a new heart or kidney. Their immune systems cannot fight off life-threatening infections without antibiotics.

• Removing a burst appendix becomes a dangerous operation once again. Patients are routinely given antibiotics after surgery to prevent the wound becoming infected by bacteria. If bacteria get into the bloodstream, they can cause life-threatening septicaemia.

• Pneumonia becomes once more “the old man’s friend”. Antibiotics have stopped it being the mass-killer it once was, particularly among the old and frail, who would lapse into unconsciousness and often slip away in their sleep. Other diseases of old age, such as cancer, have taken over.

• Gonorrhea becomes hard to treat. Resistant strains are already on the rise. Without treatment, the sexually transmitted disease causes pelvic inflammatory disease, infertility and ectopic pregnancies.

• Tuberculosis becomes incurable – first we had TB, then multi-drug-resistant TB (MDR-TB) and now there is XDR-TB (extremely drug resistant TB). TB requires very long courses (six months or more) of antibiotics. The very human tendency to stop taking or forget to take the drugs has contributed to the spread of resistance.

Options left to reverse these dire trends are limited. Possibilities described in the io9 article include the development of novel antibiotics, use of bacteriophages to combat bacterial infections, and the use of vaccines to prevent infections in the first place. The first choice (antibiotic development) does not really represent a true fix for this problem, as the use of any new antibiotics will lead to resistance of microorganisms to those new antibiotics, likely within a relatively short time frame. The only truly effective “fix” to this situation is to change how we use antibiotics in the first place.

Sexual transmission of cowpox

Site of injection of vaccinia, the vaccine for smallpox, several days after the injection. (Photo credit: Wikipedia)

Well, the title stretches this case study a bit, but it is all about drawing the reader in. I came across this story via the ever enlightening Morbidity Mortality Weekly Report, published by the Center for Disease Control and Prevention. The latest issue describes a local outbreak of vaccinia (cowpox) infections during June 2012. The first patient was admitted to a private hospital, reporting painful skin lesions. Superficially, the lesions resembled those of cowpox, and the patient reported sexual contact with someone who had been vaccinated with this virus, suggesting a route of transmission. The San Diego Public Health Laboratory then detected non-smallpox Orthopoxvirus by polymerase chain reaction (PCR) analysis to confirm the diagnosis. The patient was then treated with vaccinia immune globulin intravenous (VIGIV), a form of serum therapy, or passive immune protection against the infection. The lesions resolved without complications.

A second patient also reported skin lesions a few days later, and follow up of the case indicated that this individual’s only link to the case was sexual contact with the previous patient. This was a tertiary transmission event, from the initial vaccinated individual, to the first patient, then to the second patient. Again, vaccinia infection was verified by the Public Health lab, and treatment with VIGIV resulted in full resolution. Patient Zero was a civilian who had received the smallpox vaccine as part of the Department of Defense vaccination program. Epidemiological investigation indicated that he had only been in contact with the first patient. All patients were monitored to ensure no further transmission had occurred, particularly to at risk individuals, such as those with immunocompromised status, pregnant women, or people with chronic eczema.