Breakthroughs Blog: Zika

In this regular feature on Breakthroughs, we highlight some of the most interesting reads in global health research from the past week. In this edition, we cover new insights into the impact of the Zika virus on the brain. Researchers have released medical images of 46 fetuses and infants born to women who were infected with the Zika virus during pregnancy, revealing serious brain damage beyond microcephaly. The images, which include 23 MRI scans, 41 CT scans, and 93 ultrasounds, were taken at Instituto de Pesquisa in Campina Grande State Paraiba in northeastern Brazil and analyzed by neurologists at the Instituto in partnership with a team at the Beth Israel Deaconess Medical Center in Boston. The brain damage manifests in distinct ways: many of the scans showed skulls filled with cerebrospinal fluid, and in one case there was so little brain tissue that the skull collapsed in on itself, resulting in a flattened skull with extra skin. The images indicated damage to the brain stem, which regulates breathing and heart rate; the cerebellum, which is responsible for motor control; and the cortex, which is involved for learning, memory, emotion, and language. New research suggests that Hofbauer cells, found in the placenta and tasked with protecting the fetus from pathogens, may be the key to the Zika virus' ability to cross the maternal-fetal barrier. Hofbauer cells are macrophages, immune cells that combat pathogens by consuming them. However, dengue virus—a flavivirus related to Zika—is able to hijack macrophages, using them to replicate and disseminate throughout the body. While the researchers have confirmed that the Zika virus is able to survive within Hofbauer cells, they suspect that the immune cells may also be enabling the virus to travel to the fetal brain. The study also confirms that the virus can replicate within fibroblasts, a critical component of the placenta’s structure, a finding described as, “a bit of a surprise,” by one of the study’s authors. Scientists at Rockefeller University have also described their recent findings as "kind of a surprise," in this case, that certain adult brain cells are also susceptible to the virus. Fetal brains are primarily comprised of neural progenitor cells; while these stems cells are not as ubiquitous in adults, they play a critical role in learning and memory. Earlier this year, researchers determined that fetal neural progenitor cells are particularly vulnerable to Zika. Now, the team at Rockefeller has confirmed that adult neural progenitor cells are no exception. The study revealed an increase in cell death but a decrease in the production of new brain cells in infected adult mice. More research is needed to determine how this translates to humans, however, such damage could increase risk for cognitive challenges, depression, and Alzheimer’s disease.

Penicillin, the world’s first antibiotic, works by targeting certain proteins—appropriately named penicillin-binding proteins (PBPs)—that play a critical role in building and maintaining the bacterial cell wall. Now, scientists at Harvard Medical School have identified another class of proteins which play a similar role and could be a target for the next generation of antibiotics. The road to discovery started in 2003, when it was determined that certain bacteria could grow without PBPs. In their absence, the proteins responsible for maintaining cell wall shape, elongation, division, and spore formation (SEDS proteins) continued to function normally, enabling the bacteria to thrive. SEDS proteins are found in more types of bacteria than PBPs, and consequently a treatment targeting SEDS proteins could have even broader application than penicillin. On February 22, the Obama Administration requested US$1.9 billion in emergency funding for the Zika response, and 181 days later, Congress has yet to approve it. Consequently, the Department of Health and Human Services (HHS) has shifted $81 million from other programs to support Zika vaccine research and development—$34 million of which will go to the National Institutes of Health (NIH) and $47 million of which will be allocated to the Biomedical Advanced Research and Development Authority (BARDA). Earlier this year, HHS repurposed $589 million in funding from the Ebola response to combat Zika, however, that funding will run out by the end of this month. The NIH will use its funding for human clinical trials of its leading Zika vaccine candidate, however, the agency will need an additional $196 million for additional trials and to advance a second and third candidate. BARDA’s funding will enable the agency to secure contracts and establish partnerships for Zika vaccine development, however, an additional $342 million will be required to continue its work. New research suggests that infection with the Plasmodium parasite, which causes malaria, could reduce the severity of Ebola infection. A team of scientists at the US National Institute of Allergy and Infectious Diseases has examined 1,868 blood samples from an Ebola treatment unit in Liberia—1,182 of which tested positive for Ebola—concluding that patients co-infected with malaria were 20 percent more likely to survive. These results held true even when controlling for the patient’s age and viral load. Viral load actually correlated with survival rates: those with the highest levels of Plasmodium had an 83 percent survival rate, compared to 46 percent of those only infected with Ebola. At the treatment center, all patients were provided with antimalarials, and consequently, treatment for malaria was not responsible for survival rates. While the reason for this trend remains a mystery, Drs. Emmie de Wit and Kyle Rosenke—the study’s lead scientists—suspect that an existing malaria infection expedites the immune response to Ebola, consequently increasing survival rates.

A CDC researcher prepares reagents that would be used in a CDC-developed Zika diagnostic test. Photo: CDC/Sue Partridge, CDC- Ft. CollinsOn Wednesday, 26 current and past presidents of the American Society of Tropical Medicine and Hygiene (ASTMH) sent a letter to the leadership of the US Senate and House of Representatives urging policymakers to pass an emergency spending bill to combat the Zika virus as soon as possible, calling failure to do so “imprudent and reckless.”Six months have now passed since the White House first requested US$1.9 billion in emergency funding for the Zika virus response, yet Republicans and Democrats in Congress have failed to reach a compromise position, and last month Congress adjourned for summer recess without passing a funding bill. As a result, US agencies involved in the response, including the US Centers for Disease Control and Prevention and the National Institutes of Health, have been forced to repurpose funds from the Ebola response and other accounts to continue financing efforts to curtail the spread of the Zika virus. But President Obama and agency leaders have voiced mounting concerns that federal funds to fight Zika are quickly running out and lack of funding could delay vaccine research and development.In the letter to congressional leaders, ASTMH’s current and past-presidents note that, “The science is clear, the call to action is clear and yet, political infighting has carried the day while the outbreak continues….Patchwork and inadequate funding will not do the job—plain and simple.”The letter continues: “Without proper funding, researchers cannot sustain surveillance, planning, mosquito control, or research and development efforts to protect our most vulnerable populations, including women and children.” It ends by urging Congress to “get this job done now.” This collective leadership letter is the first of its kind for the Society, which is the largest international scientific organization of experts dedicated to reducing the worldwide burden of tropical infectious diseases and to improving global health.Click here to read the full letter.

Reducing unnecessary antibiotic use is widely considered a priority action in combating the spread of antimicrobial resistance. In the United States, one-third of antibiotic prescriptions are unnecessary and each year, there are 27 million gratuitous prescriptions for respiratory infections alone. Rapid, point-of-care diagnostics that can discern if an infection is bacterial could significantly reduce this practice, preventing antibiotic prescriptions for viral, parasitic, or fungal infections. There are now several tests in the pipeline which evaluate the level of C-reactive protein (CRP) in the bloodstream, a molecule associated with inflammation. CRP levels increase significantly in response to bacterial infections, but only slightly in response to viral infections. Not only have several of these tests proven reliable, but new research conducted by the Oxford University Clinical Research Unit in Vietnam indicates that such a test can successfully decrease antibiotic prescriptions for respiratory infections in low-resource settings. The study monitored antibiotic use for 2,000 patients at ten primary health centers, and use of the test reduced prescriptions from 78 to 64 percent, without impacting clinical recovery or patient satisfaction rates. Scientists have identified a compound that shows promise in treating three different parasitic diseases—Chagas disease, sleeping sickness, and leishmaniasis—that effect 20 million people and result in 50,000 deaths each year. The three diseases are caused by distinct parasites and transmitted by different vectors. Chagas disease results in cardiac complications, sleeping sickness causes neurological symptoms, and leishmaniasis manifests as skin sores and liver and/or spleen damage. Existing treatments are toxic, expensive, and difficult to administer in low-resource settings. The compound—GNF6702—was developed by pharmaceutical company Novartis and discovered after screening 3 million molecules in the company’s compound library. The molecule was then modified, resulting in a drug with 20 times the original potency. The compound targets proteasome—which breaks down waste—in all three parasites, but does not have the same effect in mammal cells. The drug has proven effective in mice, and will undergo additional safety tests before the initiation of human clinical trials.  The US Agency for International Development (USAID) announced last week the initial winners of its Combating Zika and Future Threats Grand Challenge, through which the agency will be providing more than US$15 million for the development and introduction of 21 innovative tools and interventions. In just two months, USAID received and reviewed nearly 900 applications, addressing various parts of outbreak prevention, detection, and control, including vector control, personal and household protection, vector and disease surveillance, community engagement, and diagnostic innovations. The winners include an electric force field to repel mosquitoes; a flip phone–based app that can distinguish between mosquito species, enabling crowdsourced vector surveillance; insecticide-treated sandals; and a human-scented mosquito trap. The agency will announce additional winners in the next month and will invest up to $30 million total.