By Harshini Mukundan
Around the world, tuberculosis is making a comeback, owing to the increased incidence of HIV/AIDS and several other factors. According to the World Health Organization (WHO), between 1900 and 2015, the incidence of new TB cases increased nearly 40 percent—from an estimated 7.5 million to 10.4 million. Furthermore, the untreatable drug-resistant strains of the bacterium are rapidly increasing, causing grave concern. In 2015, WHO estimated 480,000 new cases of multidrug-resistant TB and an additional 100,000 people with rifampicin-resistant TB. (Rifampicin is a front-line drug in TB treatment.) Drug resistance is a widespread global challenge today and could result in a post-antibiotic era, if unchecked.
That and the global health concern of TB are two reasons why our team at Los Alamos National Laboratory, in collaboration with several institutions, are working to develop an innovative tool set for early and accurate diagnosis of the disease.
One of the greatest challenges of TB is that not everyone exposed to the bacterium that causes the disease will get sick. A third of the world can harbor the bacterium, and never present with the disease: a condition called latent infection. Only under certain conditions such as when the immune system is compromised, as with autoimmune conditions or HIV/AIDS, do these individuals present with active TB. Individuals with active disease show progressively worsening symptoms of the disease, and can transmit the bug to healthy people. Another challenging aspect of TB is that it can present itself in the lungs (pulmonary infection) or in several other organs (extra-pulmonary) making diagnosis and timely treatment all the more difficult. Continue reading below ⬇️
Early, accurate diagnosis is vital in defeating TB and other deadly bacterial infections. Unfortunately, current diagnostics are either inaccurate or require extensive laboratory expertise, are time consuming, and do not discriminate between latent and active infection. This problem is especially compounded when diagnosing pediatric TB.
Several years ago, my mentor at Los Alamos National Laboratory, Dr. Basil Swanson, and I, along with our collaborators, obtained a grant from the National Institutes of Health to develop a tool that could diagnose the disease early in infection and accurately distinguish between active and latent TB. Swanson and his team had developed an extremely sensitive optical waveguide biosensor for measuring low concentrations of relevant signatures in complex biological samples such as blood. But having a sensitive platform is, in itself, not the only key to efficient diagnosis. Understanding the interaction between the bacterium and the patient, and designing efficient methods of measuring that interaction directly in clinical samples is required for success.
We have always been inspired by the rapidity, universality and efficiency with which the human immune system recognizes any infection by recognizing biomarkers—bits of a disease-causing microbe’s cells that are sloughed off in our bloodstream during active disease—and then mounts a powerful and immediate response to the invading pathogen. We wondered if we could develop a rapid diagnostic tool by mimicking this immune recognition in the laboratory, which would likely provide a universal strategy for diagnosis of all infectious diseases.
Pursuing this line of thought, we discovered that many of the bacterial biomarkers recognized by our immune receptors are sugars and fats, which hide out in our aqueous blood in “carrier molecules” such as high- and low- density lipoproteins. These are the same molecules that shuttle cholesterol within our body, and appear to function as a more generic “biological taxi service” for transporting greasy biomarkers in aqueous blood. We advanced this understanding of host-microbe interaction a step further, and developed a test to detect these greasy biomarkers directly in patient blood by exploiting their interaction with the human carrier molecules.
Our work opened the door to creating a rapid diagnostic tool, which we’ve begun testing in clinical samples. The results are exciting and, so far, extremely promising. We’ve realized that this approach can be used not just for TB, but for other pathogens as well. Our goal is to create one easy-to-use tool to diagnose all infections. Indeed, we have applied our universal approach to other bacterial infections with excellent results. I envision a day when we have a very cheap, hand-held, easy-to-use, point-of-care sensor helping patients everywhere. This research required multi-disciplinary expertise from microbiologists, chemists, engineers, spectroscopists, computational experts, and clinicians alike! We were fortunate to work with an extensive team of scientists at Los Alamos, and collaborate with an amazing array of experts from across the world, to advance our work effectively.
We’re going to need tools like this, and others too, to prevent the world from entering a post-antibiotic era where even common infections become life threatening. The choices we make and the responsibility we take now will slow the onslaught of diseases like TB, and pave the way for a healthier tomorrow.
Harshini Mukundan, Ph.D., leads the Chemistry for Biomedical Applications team within the Physical Chemistry and Applied Spectroscopy group at Los Alamos National Laboratory. She is also affiliated with the New Mexico Consortium and The University of New Mexico.