E. coli infection: Symptoms, causes, and treatment

Prior Mycobacterium Exposure Remodels Immune Cells, Impacting Tuberculosis Defense

Tuberculosis, caused by the bacterium Mycobacterium tuberculosis (Mtb) kills upwards of 1.6 million people a year, making it one of the leading causes of death by an infectious agent worldwide-;and that number is only growing larger. How, exactly, Mtb evades the immune system isn't yet known, but a collaborative team of researchers from the University of Massachusetts Amherst and Seattle Children's Research Institute recently discovered something surprising: prior exposure to a genus of bacteria called Mycobacterium seems to remodel the first-line defenders in the body's immune system. Furthermore, how those cells are remodeled depends on exactly how the body is exposed. These results, published recently in PLOS Pathogens, suggest that a more integrated treatment approach that targets all aspects of the immune response could be a more effective strategy in the fight against tuberculosis.

We breathe in thousands of liters of air every day. This essential process makes us incredibly vulnerable to inhalation of all sorts of potentially infectious pathogens that our immune systems have to respond to."

Alissa Rothchild, assistant professor in the Veterinary and Animal Sciences Department at UMass Amherst and the paper's senior author

Systems, plural. When we think of immunity, we typically think of the adaptive immune system, which is when prior exposure to a pathogen-;say, a weakened version of chickenpox-;teaches the immune system what to guard against. Vaccination is the most common tool that we use to teach our adaptive immune systems what to look out for.

While the adaptive immune system is the major focus of most vaccine research (think protective antibodies induced by COVID-19 vaccines), it is not the body's first responder-;that would be the innate immune system and its ranks of macrophages. The macrophages are the first-line defenders in the tissues that recognize and destroy pathogens and also call for backup. One way they do this by turning on different inflammatory programs that can change the tissue environment.

In the case of the lungs, these macrophages are called alveolar macrophages (AMs). They live in the lung's alveoli, the tiny air sacs where oxygen passes into the bloodstream-;but, as Rothchild has shown in a previous paper, AMs don't mount a robust immune response when they're initially infected by Mtb. This lack of response seems to be a chink in the body's armor that Mtb exploits to such devastating effect. "Mtb takes advantage of the immune response," says Rothchild, "and when they infect an AM, they can replicate inside of it for a week or longer. They effectively turn the AM into a Trojan Horse in which the bacteria can hide from the body's defenses."

"But what if we could change this first step in the chain of infection?" Rothchild continues. "What if the AMs responded more effectively to Mtb? How could we change the body's innate immune response? Studies over the last 10 years or so have demonstrated that the innate immune system is capable of undergoing long-term changes, but we are only beginning to understand the underlying mechanisms behind them."

To test conditions where the innate immune response might be remodeled, Dat Mai, a research associate at Seattle Children's Research Institute and the first author of the paper, Rothchild and their colleagues designed an experiment using two different mouse models. The first model used the BCG vaccination, one of the world's most widely distributed vaccines and the only vaccine used for tuberculosis. In the second model, the researchers induced a contained Mtb infection, which they previously showed protects against subsequent infections in a form of concomitant immunity.

Weeks after exposure, the researchers challenged the mice with aerosolized Mtb and infected macrophages were taken from each mouse model for RNA sequencing. There were striking differences in the RNA from each set of models.

While both sets of AMs showed a stronger pro-inflammatory response to Mtb than AMs from unexposed mice, the BCG-vaccinated AMs strongly turned on one type of inflammatory program, driven by interferons, while the AMs from the contained Mtb infection turned on a qualitatively different inflammatory program. Other experiments showed that the different exposure scenarios changed the AMs themselves, and that some of these changes seem to be dependent on the greater lung environment.

"What this tells us," says Rothchild, "is that there's a great deal of plasticity in the macrophage response, and that there's potential to therapeutically harness this plasticity so that we can remodel the innate immune system to fight tuberculosis."

This research, which was supported by the National Institutes of Health and the National Institute of Allergy and Infectious Disease, is part of a much bigger, global, cross-species effort to comprehensively understand the immune responses to eliminate tuberculosis, called IMPAc-TB, for Immune Mechanisms of Protection Against Mycobacterium Tuberculosis.

Dr. Kevin Urdahl, professor of pediatrics at Seattle Children's Research Institute, lead PI for this IMPAc-TB consortium, and one of the paper's co-authors, says that "the overall goal of the program is to elucidate how the immune system effectively controls or eradicates the bacteria that causes tuberculosis so that effective vaccines can be developed. This is an important part of the larger IMPAc-TB program because we will be assessing the responses of human alveolar macrophages recovered from individuals who have recently been exposed to Mycobacterium tuberculosis in a TB endemic region. The findings of Rothchild's team will help us interpret and understand the results we obtain from the human cells."

Source:

Journal reference:

Mai, D., et al. (2024). Exposure to Mycobacterium remodels alveolar macrophages and the early innate response to Mycobacterium tuberculosis infection. PLOS Pathogens. Doi.Org/10.1371/journal.Ppat.1011871.

Persian Shallot 'could Help Fight TB Antibiotic Resistance'

A type of shallot used in Iranian cooking could help "reverse the tide" of drug-resistant TB, researchers found

A type of onion could help the fight against antibiotic resistance in cases of tuberculosis, a study has suggested.

Researchers believe the antibacterial properties extracted from the Persian shallot could increase the effects of existing antibiotic treatment.

They said this could help "reverse the tide" of drug-resistant TB, which infected 490,000 people in 2016.

But they said the research was still in its early stages and clinical trials would need to follow.

In the ongoing study, led by Birkbeck, University of London and University College London, the research team conducted tests on four different molecules from the shallots, which are a staple of Iranian cooking.

They found all four showed a significant reduction in the presence of the bacteria in the multidrug-resistant TB - the most promising candidate of which inhibited growth of the isolated TB cells by more than 99.9%.

The team concluded that the chemical compounds could be used alongside existing antibiotics to combat strains of TB which have developed resistance to anti-bacterial drugs.

The team concluded that the chemical compounds may work as templates for the discovery of new drug treatment to combat strains of TB

Dr Sanjib Bhakta, one of the study's authors, from Birkbeck's department of biological sciences, said: "Despite a concerted global effort to prevent the spread of tuberculosis, approximately 10 million new cases and two million deaths were reported in 2016.

"In searching for new anti-bacterials, we tend to focus on molecules that are potent enough to be developed commercially as new drug entities by themselves.

"However, in this study we show that by inhibiting the key intrinsic resistance properties of the TB, one could increase the effects of existing antibiotic treatment and reverse the tide of already existing drug resistance."

Prof Simon Gibbons, another of the authors, and head of UCL's department of pharmaceutical and biological chemistry, said: "Natural products from plants and microbes have enormous potential as a source of new antibiotics.

"Nature is an amazingly creative chemist and it is likely that plants such as the Persian shallot produce these chemicals as a defence against microbes in their environment."

In October, England's chief medical officer, Prof Dame Sally Davies, urged global leaders to tackle the growing threat of antibiotic resistance.

Medical experts say these drugs are being used too much, and that 25,000 people die across Europe each year because of drug-resistant infections.

Researchers said they hope the molecules, which were tested in a laboratory, could be combined with existing antibiotics to form new anti-TB drugs.

The research is published in the journal Scientific Reports.

Deer Harvest Total Drops In Michigan, DNR Talks Regulations With FOX 17

GRAND RAPIDS, Mich. — Weeks before the opening day of firearm season, the Michigan DNR released a letter to the state's deer hunters.

"We need to have some frank conversations about deer management in this state," wrote Chad Stewart, the department's deer, elk, and moose management specialist.

Deer harvest total drops in Michigan, DNR talks regulations with FOX 17

In the following paragraphs, Stewart detailed a need to shoot more does than bucks, amid a decades-long decline in hunting in Michigan: "We need to quickly, and substantially, increase our antlerless deer harvest across much of our Lower Peninsula. Our reputation as conservationists may be defined by it!"

READ MORE: Michigan DNR: Try shooting a doe this deer season

Months later, with only one type of season remaining on the 2023-24 hunting calendar (extended urban archery), the state's deer harvest has again disappointed, dropping nearly 10% from the previous year.

In the 2023 license season, the DNR reported a total harvest of 274,057 deer (as of Friday), with only six counties increasing their numbers from the prior season, including Muskegon (+2%).

As for the rest of West Michigan, the harvest totals from Mecosta and Montcalm Counties both dropped 14%, while Kent and Newaygo Counties fell 12%, to name a few notables.

"We feel that we need to really try to reevaluate some of our current deer management strategies," Stewart said.

The department's goal at the beginning of deer season—that hunters take more does than bucks— also failed, with the antlerless harvest dipping to 40%, as compared to 43% from the prior year.

While Stewart admits that reporting rates may have played a role in this year's numbers, in addition to a late corn harvest that kept deer in fields, rather than hunter-filled forests, he says the department wants to "have some conversations with sportsmen" about how to reverse these trends.

"Whether you're a hunter or not, it's really incredibly important from a resource standpoint and an ecological health standpoint," Stewart said.

David Kenyon/MI Dept. Of Natural Resources

Whitetail Deer

This week, the department announced its Deer Management Initiative, a crowdsourced campaign to address declining harvest and hunting numbers.

"Some of it will be short-term fixes," Stewart said. "Some of it might be long-term fixes that we start building towards over several years."

With bovine tuberculosis and chronic wasting disease especially problematic in the Lower Peninsula, and predatory and habitat concerns in the Upper Peninsula, the DNR says members of the public can participate in the process through virtual and in-person meetings.

"I mean, not saying that things are bad, but I think there's a lot of things that need to be changed," said Dale Techel, the owner of Michigan Deer Hunters, a popular Facebook page.

The longtime hunter who lives in Southeast Michigan says the initiative should "help the communication" between hunters and the state.

I think a lot of people feel that sometimes the management of the herd isn't specific enough," said Techel, suggesting a county-by-county approach to regulation.

"People want to see deer and they want to have a healthy herd," Techel said. "I don't want to see those traditions go away, it's part of what Michigan is."

"Even if you're not a hunter, you can certainly appreciate looking at a deer and a fawn in the summertime," Stewart said. "I think there's a lot of value and a level of wildness that goes along with having that sort of experience with a white-tailed deer."

Michigan Department of Natural Resources

White-tailed deer shown in the forest

In a Friday interview, Stewart talked potential population management policies with FOX 17, including the cost of hunting licenses, buck restrictions, and the length of firearm season.

While a single kill tag deer license in Michigan costs $20 for residents and non-residents ages 10 through 64, the DNR does sell $5 licenses in Deer Management Unit 487, a multi-county stretch of land in the Northern Lower Peninsula, particularly affected by bovine tuberculosis.

Despite the cheaper price tag, Stewart hasn't seen an increase in the harvest.

"Does that apply to other parts of the state? Maybe, maybe not," Stewart said, admitting that the current license structure "certainly needs to be reviewed" by the initiative.

As for introducing additional antler-point restrictions, Stewart said they were "absolutely on the table" and "worth discussion." But he noted that an earn-a-buck rule may not be popular with hunters, citing how Michigan's Midwest neighbor, Wisconsin, banned the measure after its institution.

"When we talk about regulations, we have to talk about not only the biological impact, but also the social acceptance of them," Stewart said.

U.S. Fish and Wildlife Service

The length and purpose of the different types of deer seasons have also been critiqued, and Stewart says the typical suggestions— extending firearm season and turning the youth hunt into antlerless-only— likely won't matter.

"The more days you add onto the end, it's really more of a diminishing return," he said, citing a "majority" of deer being within the first few days of any season.

Regarding the youth hunt, the number of deer taking during the short season is so small, he says any restrictions on bucks would not be "impactful whatsoever" from a biological perspective.

"It really comes down to education and mentorship," Stewart said about the next generation of hunters in Michigan. "We're talking about getting a whole lot of people together and tasking them with changing deer management dramatically."

"That's a really ambitious goal."

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