Antiretroviral therapy of pregnant women and antiretroviral treatment of infants have greatly reduced the rate of mother-to-child HIV transmission, also referred to as vertical transmission. Nevertheless, although these improved rates have occurred in some countries, vertical transmission rates remain relatively high in others. This may be due to multiple factors, including access to testing, care and antiretroviral therapy, adherence to antiretroviral therapy during pregnancy and breastfeeding, and potential HIV drug resistance. In order to evaluate the factors that result in vertical transmission, researchers compared variables that resulted in HIV outcomes in infants from pregnant and breastfeeding mothers from 14 sites in 7 countries.

The researchers analyzed plasma from mothers and their infants at or near the time of infant HIV diagnosis to determine whether their infections were resistant to currently used drugs. Additionally, the researchers did long-term analysis of the HIV genetic structure in the infants so that they could analyze possible drug resistance later on. Their findings showed that maternal HIV drug resistance was not associated with in utero vertical transmission. However, both maternal viral load and HIV drug resistance were associated with vertical transmission during breastfeeding. These findings support efforts to reduce and eliminate HIV reproduction during pregnancy and have implications for re-evaluating appropriate antiretroviral treatment for breastfeeding infants.

Reference: Boyce et al.  Maternal Human Immunodeficiency Virus (HIV) Drug Resistance Is Associated With Vertical Transmission and Is Prevalent in Infected Infants, Clinical Infectious Diseases, 2021; ciab744.

The first Food and Drug Administration approval of a treatment for eosinophilic esophagitis, announced in May 2022, marked a vital achievement not only for people with the disease, but also for scientists including a NIAID grantee whose research helped lay a foundation for this milestone.

Eosinophilic esophagitis, or EoE, is a chronic disease characterized by an overabundance of a specific type of white blood cell, an eosinophil, in the esophagus. The disease is driven by allergic inflammation due to food. This inflammation damages the esophagus and prevents it from working properly. For people with EoE, swallowing even small amounts of food can be a painful and worrisome choking experience. EoE is the most common reason people must go to emergency departments for a healthcare provider to remove food stuck in their esophagus. People with EoE are often left to contend with the frustration and anxiety of a sometimes-lengthy list of foods to avoid, a poor quality of life, and a higher risk of depression. In severe cases, a feeding tube may be the only option to ensure proper caloric intake and adequate nutrition. About 160,000 people in the United States are living with EoE.

NIAID funding enabled Marc E. Rothenberg, M.D., Ph.D., at Cincinnati Children’s in Ohio to conduct basic and preclinical research starting in 1999 that uncovered the molecular cause of EoE. This finding suggested the type of drug needed to treat the disorder.

Before 2001, some in the medical community thought EoE was a form of acid reflux disease. Dr. Rothenberg’s lab published a paper that year establishing that EoE is actually an allergic disorder. The paper showed that mice exposed to an inhaled respiratory allergen developed EoE. This helped focus subsequent studies of EoE on the role of allergic inflammation.

A few years later, two seminal papers from Dr. Rothenberg’s lab identified the molecular changes taking place in the esophagus of people with EoE and showed that a cell-signaling molecule called IL-13 was responsible for many of those changes. IL-13 and another cell-signaling molecule, IL-4, together drive allergic inflammation in many diseases.

The first of these two key papers reported the results of an analysis of gene expression in cells on the lining of the esophagus in people with and without EoE. The study identified 574 genes that were copied into RNA “transcripts”—the instructions for making proteins—in greater or smaller numbers in people with EoE than in healthy people. This EoE transcript signature, or transcriptome, served as a key reference for subsequent studies of the disorder.

The second paper demonstrated in 2007 that many of the EoE-associated genes identified in the earlier paper are directly activated by IL-13 in cells lining the esophagus, implicating this molecule as a major regulator of the biological pathways involved in EoE. This finding suggested that IL-13-blocking drugs might effectively treat the disease. The study further showed that 98% of the EoE transcriptome reverted to normal levels of gene expression in people whose EoE was successfully treated with a class of steroid hormones called glucocorticoids. This indicated that the EoE transcriptome changes in response to changes in signs and symptoms of the disease. Dr. Rothenberg and colleagues therefore proposed using the EoE transcriptome to monitor the efficacy and mechanism of action of IL-13-blocking drugs at the molecular level.

Several years later, Dr. Rothenberg designed and led the first clinical trial to test the efficacy of an anti-IL-13 monoclonal antibody for treating EoE. The investigators found that the antibody lowered levels of eosinophils in the esophagus and returned the expression of 29 key genes in the EoE transcriptome to normal levels in most treated participants. This and related molecular analyses from the trial, funded by Novartis Pharma AG of Basel, Switzerland, further supported Dr. Rothenberg’s theory that EoE was driven by IL-13.

These findings contributed to a body of foundational EoE research developed by a multitude of scientists and physicians. This scientific foundation, among many other factors, led Regeneron Pharmaceuticals Inc. of Tarrytown, New York, and Sanofi of Paris to begin testing one of their drugs for the treatment of EoE. The drug, a monoclonal antibody called dupilumab, works by blocking both IL-13 and IL-4.

Ultimately, Regeneron and Sanofi conducted a Phase 3 clinical trial showing dupilumab substantially improved the signs and symptoms of EoE compared to a placebo. Based on these results, FDA approved dupilumab for the treatment of the disease on May 20, 2022, making it the first medicine specifically indicated to treat EoE in the United States.

NIAID-funded basic and translational research continues to contribute to the development of preventive and therapeutic strategies for dozens of allergic, immunologic, and infectious diseases.

References:

A Mishra, et al. An etiological role for aeroallergens and eosinophils in experimental esophagitis. The Journal of Clinical Investigation DOI: 10.1172/JCI10224 (2001).

C Blanchard, et al. Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis. The Journal of Clinical Investigation DOI: 10.1172/JCI26679 (2006).

C Blanchard, et al. IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2007.10.024 (2007).

ME Rothenberg, et al. Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis. Journal of Allergy and Clinical Immunology DOI: 10.1016/j.jaci.2014.07.049 (2015).

This blog is adapted and cross-posted from HIV.gov.

HIV.gov continued daily coverage of AIDS 2024. Below are recaps of four livestreamed conversations:

NIH Research Updates

Brian Minalga, M.S.W., deputy director of the NIH-supported Office of HIV/AIDS Network Coordination, spoke with Carl Dieffenbach, Ph.D., director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Diseases. They discussed the importance of including people who inject drugs in HIV research because the population is disproportionately affected by HIV and currently underrepresented in clinical studies. They highlighted the current HIV Prevention Trials Network 103 study of long-acting lenacapavir for HIV pre-exposure prophylaxis (PrEP) in people who inject drugs in the United States.

They also discussed the NIH-supported HIV clinical trials networks, and the process underway to plan for the next ten years of HIV clinical research through networks. They both emphasized that the networks not only continue to advance HIV research, but they also serve as a platform for responding to urgent health threats affecting people with and without HIV, such as mpox and COVID-19.

Learn more about their conversation below:

Following the presentation of promising results from the PURPOSE 1 study of twice-yearly lenacapavir for HIV PrEP in cisgender women in South Africa and Uganda, several HIV leaders gathered to discuss the implications of the findings for HIV prevention. Dr. Dieffenbach, Jonathan Mermin, M.D., M.P.H., director of CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, and PACHA member Tori Cooper shared their thoughts.

The PURPOSE 1 presentation showed lenacapavir was 100% effective at preventing HIV in cisgender women when compared to the estimated HIV incidence in the general population in the study countries. The group discussed how a twice-yearly PrEP could overcome barriers to use for some people and reduce the number of healthcare visits needed for people using PrEP. They also reminded viewers that lenacapavir is not yet approved for use.

They also discussed another study, PURPOSE 2, which examined the efficacy and safety of lenacapavir for PrEP among gay and bisexual men, transgender women, and nonbinary people who have sex with people assigned male a birth. Finally, they discussed outstanding questions from the PURPOSE 1 study, including the need to better understand why two daily oral PrEP formulations that were also examined in the study did not show a preventive effect.

HIV Criminalization Laws

Earlier in the day, HIV.gov director Miguel Gomez asked Francisco Ruiz, White House Office of National AIDS Policy Director, Janet Butler-McPhee of the HIV Legal Network, and Robert Suttle of the Elizabeth Taylor AIDS Foundation to share their thoughts about the opening plenary on HIV criminalization laws. The panelists discussed how outdated and unscientific laws add to stigma and discrimination against people with HIV and drive new HIV transmissions. The conversation also focused on reasons to be hopeful about progress being made.

Learn more about their conversation below:

PEPFAR and Safe, Responsible Use of AI

Miguel also spoke with Mike Reid, M.D., chief science officer in the U.S. Department of State’s Bureau of Global Health Security and Diplomacy – PEPFAR, about the safe, responsible use of artificial intelligence (AI). Dr. Reid said PEPFAR is looking at the transparent and incremental ways to implement AI to advance the program’s strategic goals. PEPAR will participate in a workshop on Thursday at IAS highlighting several use cases of AI.

Learn more about their conversation below:

Check out all of the AIDS 2024 blogs 

AIDS 2024: NIH Research Updates, Inequities, U=U, and Doxy PrEP (VIDEO), July 24, 2024

Do you know some people who almost never get sick and bounce back quickly when they do, while other people frequently suffer from one illness or another? NIAID-supported researchers have pinpointed an attribute of the immune system called immune resilience that helps explain why some people live longer and healthier lives than others.

Immune resilience involves the ability at any age to control inflammation and to preserve or rapidly restore immune activity that promotes resistance to disease, the investigators explain. They discovered that people with the highest level of immune resilience lived longer than others. People with greater immune resilience also were more likely to survive COVID-19 and sepsis as well as to have a lower risk of acquiring HIV infection and developing AIDS, symptomatic influenza, and recurrent skin cancer. In addition, women were more likely to have optimal immune resilience than men. These findings suggest that knowing an individual’s level of immune resilience could help healthcare providers assess the risk for a severe outcome in people with immunity-dependent diseases and identify mechanisms to extend lifespan, according to the investigators. The NIAID co-funded research was published today in the journal Nature Communications.

The nine-year study was led by Sunil Ahuja, M.D., the President's Council/Dielmann Chair for Excellence in Medical Research and professor of medicine at the University of Texas Health Science Center at San Antonio. Dr. Ahuja is also director of research enhancement programs at the university and director of the Veterans Administration Center for Personalized Medicine in the South Texas Veterans Health Care System in San Antonio.

Measuring Immune Resilience

Dr. Ahuja and colleagues developed two ways to measure immune resilience, or IR, one based on immune-cell levels in blood and the other on patterns of genes that are turned on, or expressed. The investigators evaluated these metrics in roughly 48,500 people ages 9 to 103 years who were exposed to pathogens and other immune-system stressors of varied types and severity levels, including the natural aging process. The data on these people, who were Black, Hispanic, or White, came from more than 18 different studies conducted in Africa, Europe, and North America.

One of the two IR metrics—the immune health grade, or IHG—is based on the relative quantities of two types of white blood cells, CD8+ T cells and CD4+ T cells, which coordinate the immune system’s response to pathogens and kill other cells that have been infected. CD4+ T-cell counts in the blood have long been used to measure immune health, particularly in people with HIV. The IHG is innovative because it reflects the balance between CD8+ and CD4+ T-cell counts. The CD8+ to CD4+ T-cell balance in optimal IR is called IHG-I, while less optimal levels of IR are called IHG-II, IHG-III and IHG-IV.

The second IR metric is based on two patterns of gene expression: one that best predicted survival and another that best predicted death in two large groups of people after controlling for age and sex. The researchers labeled the survival-associated pattern SAS-1 and the mortality-associated pattern MAS-1. SAS-1 genes are largely related to immune competence—the ability to preserve or rapidly restore immune activity that promotes resistance to disease. MAS-1 genes are largely related to inflammation—the process by which the immune system recognizes and helps kill or remove pathogens and other harmful or foreign substances and begins the healing process. The scientists found that high levels of SAS-1 gene expression and low levels of MAS-1 gene expression indicated that a person had optimal IR and a lower risk of dying prematurely, while the opposite indicated poor IR and a higher risk of premature death. If SAS-1 and MAS-1 levels were both high or both low, IR and risk of premature death were moderate.

The investigators tested these two sets of metrics—IHGs and SAS-1/MAS-1—in the context of low-, moderate- and high-intensity stress to the immune system to determine how well the measures predicted health outcomes and lifespan after controlling for age and sex. The scientists identified groups of people experiencing these different intensities of immune challenges in the context of their daily lives. The group experiencing low-intensity immune stimulation comprised thousands of HIV-negative people ages 18 to 103 years participating in long-term studies of aging. The group experiencing moderate-intensity immune stimulation involved hundreds of HIV-negative people with SARS-CoV-2 infection, autoimmune disease, kidney transplant, or behavioral risk factors for acquiring HIV. Finally, the group experiencing high-intensity immune stimulation comprised thousands of people whose immune systems were responding to HIV replication in the blood soon after infection.

Variations in Immune Resilience

The researchers found that preserving optimal IR, as indicated by having either IHG-I or the combination of high SAS-1 and low MAS-1, was associated with the best health outcomes and longest lifespans. In addition, the risk or severity of negative immunity-dependent health outcomes increased as baseline IR level decreased. The scientists also demonstrated that the proportion of people with optimal IR (IHG-I or high SAS-1/low MAS-1) tended to be highest in the youngest people and lowest in the oldest people. Similarly, the proportion of people with the least optimal IR metrics (IHG-III or IHG-IV and low SAS-1/high MAS-1) tended to be lowest in the youngest age groups and highest in the oldest age groups. However, the investigators found that each of the four immune health grades and related SAS-1/MAS-1 gene expression profiles appeared in people in every age group.

As people age, the researchers explained, increasingly more health conditions such as acute infections, chronic diseases and cancers challenge their immune systems to respond and—ideally—recover. Over time, these challenges degrade most people’s immune health, accounting for the declining proportion of people with IHG-I and high SAS-1/low MAS-1 over the lifespan. However, some people who are 90 years old or more still have IHG-I and high SAS-1/low MAS-1—a reflection of their immune systems’ exceptional capacity to control inflammation and preserve or rapidly restore immune activity associated with longevity despite the many immune health challenges they have faced.

By contrast, the researchers demonstrate that some young adults who are repeatedly exposed to immune threats may have the least optimal IR, as measured by IHG-III or IHG-IV and low SAS-1/high MAS-1. The investigators show how young female sex workers who had many clients and did not use condoms—and thus were repeatedly exposed to sexually transmitted pathogens—had drastically degraded immune health even if they did not acquire HIV. In addition, sex workers with nonoptimal IR, especially those with IHG-IV, had a higher risk of acquiring HIV infection regardless of their level of risk behavior. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners improved to IHG-I over the next 10 years.

The scientists also observed this plasticity of IR in other contexts. For example, the researchers found that most people couldn’t maintain optimal IR when they experienced inflammatory stress from a common symptomatic viral infection like a cold or the flu. In this situation, most people who the investigators studied developed low SAS-1/high MAS-1 within 48 hours of symptom onset, indicating poor IR and a high risk of dying prematurely. As people recovered from their infection, however, many gradually returned to the more favorable SAS-1/MAS-1 levels that they had before. Yet nearly 30 percent of those who had high SAS-1/low MAS-1 before getting sick did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.

Interestingly, the investigators also found that the ability to maintain or develop optimal IR during a respiratory virus infection, as measured by high SAS-1/low MAS-1, correlated with an absence of symptoms.

Implications of Immune Resilience

The researchers suggest numerous implications of their findings for personalized medicine, biomedical research, and public health. First, some younger adults have low IR due to unsuspected immunosuppression, whereas some older adults have superior IR. These differences may account for why some younger people are predisposed to disease and shorter lifespans while some elderly people remain unusually healthy and live longer than their peers. Second, reducing exposure to immune stressors may maintain optimal IR or give people with low or moderate IR the opportunity to regain optimal IR, thereby decreasing risk of severe disease. Third, measuring people’s IHG and SAS-1/MAS-1 profile in the early stages of illness could allow for detection of poor IR and initiation of more aggressive therapy. Fourth, it may make sense to balance the intervention and placebo arms of clinical trials by both IR status and common factors such as age and sex when testing interventions dependent on controlling inflammation and preserving or rapidly restoring immune activity associated with longevity. Fifth, developing and implementing strategies to mitigate IR degradation may improve people’s response to vaccination as well as their overall health and lifespan. Finally, strategies for boosting IR and reducing recurrent immune stressors may help address racial, ethnic, and geographic disparities in diseases such as cancer and viral infections like COVID-19.

Reference: SK Ahuja, et al. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Nature Communications DOI: 10.1038/s41467-023-38238-6 (2023).

Mosquito-borne diseases include some of the most important human diseases worldwide, such as malaria and dengue. With global temperatures increasing because of climate change, mosquitoes and the pathogens they transmit are expanding their range. For example, the Centers for Disease Control and Prevention recently reported a number of malaria and dengue cases transmitted within the United States in Texas and Florida. Therefore, it has become more urgent to understand the interactions between climate, mosquitoes, and the pathogens mosquitoes transmit to humans.

The National Institutes of Health (NIH) Climate Change and Health Initiative is a collaborative effort across NIH Institutes and Centers to reduce the public health impact of climate change. As part of the Initiative’s Scholars Program, NIH brings climate and health scientists from outside the U.S. federal government to work with NIH staff to share knowledge and help build expertise in the scientific domains outlined in the Initiative’s Strategic Framework. 

Luis Chaves, Ph.D., is a 2023 Scholar working with NIAID. Dr. Chaves is an associate professor in the Department of Environmental and Occupational Health in the School of Public Health-Bloomington, Indiana University, and was previously an associate scientist at the Instituto Gorgas in Panama. His research focuses on understanding the impacts of environmental change on the ecology of insect vectors and the diseases they transmit. Over the last 20 years, he has combined field studies and modeling approaches, both statistical and mathematical, to address how insect vectors respond to changes in the environment and how these changes impact the transmission of diseases, such as malaria and dengue. NIAID spoke with Dr. Chaves about his work. 

Note: responses to the questions have been edited for clarity and brevity.

In what ways have you seen climate changes impact vectors and disease transmission?
There is very strong evidence that climate change has affected vector-borne diseases. This includes mosquito-borne diseases, like malaria and dengue, but also other diseases like leishmaniasis, which is transmitted by sandflies. Changes in temperature and rainfall affect the spread of disease vectors and impact their breeding behavior. For example, there is evidence of the impact of El Niño weather events on malaria transmission. Higher temperatures and more rainfall make a more suitable habitat for mosquito breeding, causing an increase in disease transmission. In other areas, El Niño weather patterns are associated with droughts, which may reduce disease transmission but cause food shortages. These weather patterns have been known and studied before, but climate change has generated more extreme conditions resulting in more extreme weather events. So, we can see that there is robust evidence that climate change is having a massive impact on human health and wellbeing.

What sparked your interest in examining how socio-economic conditions impact vector-borne disease transmission and control? 
I remember the first encounter I had with Chagas disease was visiting an uncle who lived in a rural setting. I was told not to visit a neighbor’s house because they had Chagas disease. There were lots of discussions about how his neighbor got Chagas because his home was made from mud, which is why kissing bugs, the vectors of Chagas disease, got inside. That was the first time I observed an increased prevalence of diseases in places with social exclusion and poverty. More generally, infectious diseases cannot be put out of the social and economic context where they emerge and are transmitted. If you have people with substandard housing, is that a choice, or a constraint because of the underlying socio-economic inequities? It is impossible to learn about the ecology of disease transmission without understanding that the ecology of transmission is not only ecological and environmental but also social. 

What are the advantages of using mathematical modeling to study vector-borne diseases?
Mathematical and quantitative modeling have been incredibly useful to expand the ways in which the relations shaping disease patterns can be studied This ability to understand interactions advances our capacity to engage in more relational science, where factors aren’t understood as fixed and independent forces, but as dynamic and interdependent. Relations between variables can’t be described by a fixed constant proportion, but by nonlinearities that can be easily grasped by machine learning algorithms and other data science tools.  Computers have made it easier to collect, process and analyze larger datasets. The automation of data assimilation using pipelines that integrate different data sources and algorithms can lead to robust “boosted” predictions about where and when to expect the transmission of some vector-borne diseases. Mathematical models also show how the stability of natural systems can collapse following small changes in the environment, and that has clear implications about why we need to worry as climate change continues its current course.   

What limitations do you see in the use of data science?
Data science poses ethical dilemmas, because not everyone mining freely available data is likely to do so with altruistic aims, nor is it clear how communities and individuals could benefit from the data they generated when someone profits from that or how communities, and even individuals, are protected from potential misuse.  I also think there is a need to always consider the context in which data are generated, as this approximation allows us to see what else is out there. The more nuanced our knowledge is, the more likely we can generate actionable knowledge that improves human health and wellbeing. That’s why it’s so important to include information on how data is collected (metadata) and how to use it.  The nuances don’t come from just looking at the data. They require experience, observation, and immersion in nature to create a clearer picture of vector-borne disease transmission. 

How has your work influenced vector control and prevention activities?
My research at the Costa Rican Institute for Research and Training in Nutrition and Health’s (INCIENSA) and the Costa Rican Vector Control Program was centered around developing insect vector maps and training people working in vector control about the impacts of climate change. This also involved evaluating past policies and their impact on parasitic and neglected tropical diseases. For example, comparing how different public health strategies like Mass Drug Administration versus vector control might impact malaria transmission and elimination. These activities increased the awareness about the importance of climate change, particularly among vector control inspectors, with whom I interacted closely on their work.  My research has also supported a focus on Mass Drug Administration as a major tool to eliminate malaria in Costa Rica.

What impact do you hope your research will have?
I’ll be happy if my research can serve, at least, the communities where the research is being done. As long as my research can lead to diminishing transmission of infectious pathogens or reducing the populations of vectors, then I will be happy. If that eventually leads to the elimination of those diseases, I’ll be even happier. I want to be able to provide resources for the local communities, so they can understand health problems or health threats within their local environment. For example, one of the nicest experiences I have had as a researcher was in Panama, where at least three or four studies on leishmaniasis have been done in the same community. In that community, we have seen how people come up with their own solutions, partly based on what they learn from when you did research in that location. You see how they modify their houses and look for changes in incidence of new cases. When they tell you that cases of leishmaniasis have gone down, that newborns and children aren´t getting the disease, that is very fulfilling.                     

Certain species of fungi are responsible for many common infections including yeast infections, ringworm, thrush, and athlete’s foot. While these diseases may not lead to serious outcomes for most healthy individuals, fungal infections can be deadly, especially for patients with weakened immune systems. One fungal pathogen, Candida auris, is an emerging healthcare-associated infection of growing public health concern. The first case of Candida auris was reported in 2009 in Japan, where it was isolated from a patient’s ear (Auris is Latin for “ear”). Outbreaks have since emerged rapidly around the globe. In the United States, C. auris infections have been increasing over the past few years, with more than 1460 cases reported in 2021. C. auris is typically found in hospitals and other healthcare settings and can cause serious bloodstream and wound infections.

Like other Candida species, C. auris is a type of yeast. However, unlike its yeasty cousins, this pathogen can colonize patients’ skin and persist for long periods of time on environmental surfaces. Another challenge is that C. auris is often resistant to one or more of the major classes of drugs that are typically used to treat fungal infections. While most C. auris infections can be treated with a class of antifungals called echinocandins, resistance to these drugs has also been reported, making some infections difficult to treat. C. auris is the only fungal pathogen identified as an ‘urgent’ threat in CDC’s Antibiotic Resistance Threat Report.

Back to basics

NIAID supports several researchers who are asking fundamental questions about the biology of C. auris. Today’s NIAID Now post features insights from NIAID-funded researchers, Jeniel Nett, M.D., Ph.D., associate professor of medicine and medical microbiology and immunology at University of Wisconsin-Madison, and Christina Cuomo, Ph.D., associate director of the Genomic Center of Infectious Diseases at the Broad Institute of Massachusetts Institute of Technology and Harvard University.

How is C. auris able to colonize the skin and persist in the environment?

C. auris can live and grow on the skin or in the body without causing illness. However, people who are colonized with C. auris may spread the pathogen to others and are at risk of getting sick later on if they develop infections. One important question to understanding C. auris outbreaks is: how is the fungus able to colonize skin so effectively and to persist in the environment? Dr. Nett’s research group is tackling this question by studying C. auris growth in the lab using two different systems. The first is designed to mimic human sweat and skin. Nett noted, “we think that this represents skin to some degree but also when surfaces get contaminated with skin and sweat components.” The other system is pig skin. “Pigs have similar skin to humans in terms of skin thickness and some of the cell types,” Nett explained. Using these systems, Nett and colleagues have shown that C. auris is able to readily grow on skin. “It really seems to mirror what we’re seeing patients,” said Nett. They’ve found that when the fungus is grown in the synthetic sweat medium, it forms multi-layered plaques, or biofilms, both on the pig skin as well as on hard surfaces. Compared to other Candida species, the biofilms are thicker and contain more viable organisms. C. auris biofilms can also persist on surfaces without drying out for up to two weeks in the lab.

Jeniel Nett, M.D., Ph.D., associate professor of medicine and medical microbiology and immunology at University of Wisconsin-Madison

Credit: Dr. Jeniel Nett

Nett’s research demonstrates the ability of the fungus to colonize skin and form persistent biofilms on environmental surfaces, which has implications for transmission in healthcare settings. “This really becomes important with reusable medical equipment that goes room to room,” Nett emphasized. The systems Nett’s group has developed to study C. auris in the lab can also inform potential strategies to remove C. auris from the skin of patients. Nett’s research has shown that while antiseptics are somewhat effective, they are not as active against C. auris when the fungus is growing in the skin environment compared to when it is growing without the skin present. In a published manuscript, Nett and colleagues demonstrated that the commonly used topical antiseptic chlorhexidine does not fully remove C. auris from the skin of patients. They also showed that by adding isopropanol, as well as some essential oils, including tea tree and lemongrass, to chlorhexidine, they were able to improve the activity of the antiseptic. Her group is still investigating what specific components of skin and sweat are triggering biofilm growth in C. auris. Understanding this could lead to better, more specific strategies to disrupt skin colonization.

How did C. auris outbreaks emerge around the world, and how has the fungus become multidrug-resistant?

Soon after it was first identified, outbreaks of C. auris arose in four distinct locations—South Asia, East Asia, Africa, and South America—nearly simultaneously. Dr. Cuomo and colleagues are using a genomics approach to better understand this phenomenon. 
“One fundamental question genomics can answer is, what has been the history of the pathogen over time?” Cuomo explained. “We can take isolates from different patients, and by comparing them we can infer back in time to where they have a common connection.”

Christina Cuomo, Ph.D., associate director of the Genomic Center of Infectious Diseases at the Broad Institute of Massachusetts Institute of Technology and Harvard University

Credit: Dr. Christina Cuomo

Together with colleagues at the Centers for Disease Control and Prevention, Cuomo’s group helped confirm that the different outbreaks were caused by distinct genetic groups, or ‘clades.’ As cases have continued to spread around the globe, researchers have been able to trace new C. auris isolates back to these four major clades, allowing them to understand how the different outbreaks are connected.

Expanding on this initial work, Cuomo’s group is looking more closely at the different C. auris clades and identifying key genetic differences both within and between these groups as well as among C. auris and other related Candida species. From this analysis, they have generated hypotheses about which genes in the fungus are important for contributing to disease in humans. Such studies provide important insight into the biology of C. auris and can help identify potential targets for new drugs.

Researchers are also actively trying to understand how this fungal species has evolved to become resistant to certain antifungal drugs. Combining clinical data and experimental evolution studies, Cuomo’s group has identified specific mutations, or genetic changes, contributing to resistance to the major classes of antifungal drugs, including echinocandins. Cuomo explained that a single change in one of the C. auris proteins causes the fungus to go from sensitive to resistant, which explains why patients will sometimes stop responding in the middle of treatment with echinocandins.

The genomic resources that Cuomo and her group have developed are used by public health laboratories to help assess the frequency of drug resistance in C. auris. Understanding what genetic changes are associated with drug resistance can also help inform patient treatment. “That’s the kind of information we want to be marrying to traditional diagnostics, to think about how can we best type resistance across the course of a patient’s treatment,” Cuomo noted. “We know that resistance can arise while on treatment. We’d like to detect that as soon as it emerges, and not when the patient succumbs to a very high fever or other devastating symptoms.”

From knowledge to solutions

Working on a novel pathogen is a challenging effort. Both Drs. Nett and Cuomo have forged into relatively new scientific territory, and have had to develop new tools, methods, and resources to study C. auris. However, their work has the potential to make a significant impact against this emerging disease. While the scientific questions they both are tackling are fundamental in nature, the answers are of critical importance to patient care and public health interventions.

Learn more about this research by reading recent papers from Dr. Nett, Dr. Cuomo, and colleagues:

CJ, Johnson et al. Modeling Candida auris skin colonization: Mice, swine, and humans. PLOS Pathogens. DOI: 10.1371/journal.ppat.1010730 (2022)

JM Rybak et al. In vivo emergence of high-level resistance during treatment reveals the first identified mechanism of amphotericin B resistance in Candida auris. Clin Microbiology Infect. DOI:10.1016/j.cmi.2021.11.024 (2022). 

C Johnson et al. Augmenting the Activity of Chlorhexidine for Decolonization of Candida auris from Porcine skin. J Fungi. DOI: : 10.3390/jof7100804 (2021).

J Muñoz et al. Clade-specific chromosomal rearrangements and loss of subtelomeric adhesins in Candida auris. Genetics. DOI: : 10.1093/genetics/iyab029 (2021). 

N Chow et al. Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses. mBio. DOI: : 10.1128/mBio.03364-19 (2020). 

M Horton et al. Candida auris Forms High-Burden Biofilms in Skin Niche Conditions and on Porcine Skin. mSphere. DOI : 10.1128/mSphere.00910-19 (2020).

S Lockhard et al. Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis. DOI: 10.1093/cid/ciw691 (2017) 

Eix EF, CJ Johnson, KM Wartman, JF Kernien, JJ Meudt, D Shanmuganayagam, ALF Gibson, JE Nett. 2022. Ex vivo human and porcine skin effectively model C. auris colonization, differentiating robust and poor fungal colonizers. J Infect Dis. PMID: 35267041