Cytomegalovirus as a risk factor for TB and leishmaniasis

Led by Dr Lisa Stockdale (University of Oxford, UK), with Dr Robindra Basu Roy (LSHTM, UK), Dr Vivian Tamietti Martins (Federal University of Minas Gerais, Brazil), Assoc Prof Eduardo Coelho (Federal University of Minas Gerais, Brazil), and Prof Helen Fletcher (LSHTM, UK)

Project Aims

Tuberculosis and leishmaniasis are diseases that particularly affect some of the world's poorest populations. Caused by the microbes Mycobacterium tuberculosis and the microscopic parasite Leishmania spp. respectively, control of these diseases is hampered by a lack of effective vaccines. The drugs that are available require long regimes, have significant side effects, and treatment is complicated by antimicrobial resistance. In 2018, TB overtook HIV/AIDS as the largest cause of mortality due to a single infection, and visceral leishmaniasis (VL; the most serious form of the disease) is fatal in 95% of cases if left untreated.

The role of an accompanying viral infection influencing the development of TB and VL is well-known through the increased risk in People Living With HIV. Cytomegalovirus (CMV), another virus, has also recently been implicated in increased risk of TB disease. Our current understanding of TB and leishmaniasis is that the body's protective immune responses are skewed, enabling the microbes to remain in the body and cause disease. One of the immune molecules involved in this balance between pathogen persistence and pathogen clearance for both diseases is IL-10. It is linked with shifting this balance towards disease persistence. CMV has its own viral version of this molecule which acts similarly to human IL-10.

Using three unique sample sets to investigate risk of infection with TB in Gambian children, risk of developing TB disease in Ugandan people, and severity of leishmaniasis in Brazilian people, we hope to understand if and how CMV is implicated in increased risk of infection and disease. Not only will this information help to direct future VL and TB vaccine development but it may also drive development of a CMV vaccine as a possible cross-pathogen contribution to control of both diseases.

Project Outcomes

This project aimed to investigate the link between tuberculosis (TB), leishmaniasis and the ubiquitous human herpes virus, cytomegalovirus (CMV). TB and leishmaniasis are diseases that particularly affect some of the world’s poorest populations.

Previous research found a link between CMV infection and increased risk of, and reduced time to development of, TB disease. Despite also being an intracellular pathogen with immunological parallels to TB pathogenesis, the role of co-infection of CMV in leishmaniasis has not been investigated. Our current understanding of progression of both TB and leishmaniasis is characterised by dysregulation of protective immune responses in favour of an immune environment conducive to pathogen persistence. CMV is widely distributed in human populations and infection is highly associated with immune variation and activation. It is also linked to a range of chronic diseases, and increased overall mortality. CMV vaccine development is already underway, however based upon a small target population (women of childbearing age to protect neonates from CMV-associated neurological disorders), progress is slower than it might be if CMV were found to be a risk factor for other infections.

Using 3 unique sample sets to investigate risk of infection with TB in Gambian children, risk of developing TB disease in Ugandan people, and severity of leishmaniasis in Brazilian people, this project measured humoral responses to CMV infection along with markers of inflammation, a human and viral version of the cytokine IL10, and Th1 and Th2 cytokines.

Among Gambian children, highly-TB exposed uninfected children had higher levels of CMV IgG than matched (on exposure to TB) infected children, suggesting that infection with CMV may not play as big a part in risk of initial infection with M.tb as compared with progression to TB disease once infected. Only 4/52 individuals had measurable levels of CMV vIL10. All 52 individuals were positive for CMV IgG suggesting that 100% of children in this cohort had been infected with CMV at some point. Only 7/52 individuals were positive for CMV IgM which is a marker of current or recent infection, however markers of general inflammation were not elevated for those 7 individuals compared with the rest of the cohort.

Among individuals recruited to a rural Ugandan case-control study, we found a dose-response between odds of progression to active TB disease and increased levels of CMV IgM, CMV IgG avidity and CRP levels. Significant positive correlations were seen between CMV IgG avidity and CMV IgG antibody levels, between measures of inflammation and CMV IgG, and between Th2 cytokines IL4 and IL13. Despite this, the dose response associations were not altered by the addition of CMV IgG levels into a regression model. No samples had detectable CMV vIL10 levels.

Among Brazilian leishmania patients, all the visceral leishmanisis patients were CMV IgG positive, 49/50 tegumentary leishmaniasis patients were CMV IgG positive, and 36/50 control individuals were CMV IgG positive. Individuals with tegumentary leishmaniasis had significantly higher levels of CMV IgG compared with visceral leishmania patients, and both groups had significantly higher CMV IgG compared with control individuals without leishmania infection. None of the control individuals, and only 3/50 tegumentary and 3/50 visceral leishmaniasis patients were positive for CMV IgM. Further data is awaited from the Brazilian cohort.

In summary, this project has found further evidence that CMV may be associated with TB disease in a Ugandan population and found preliminary evidence of an association between CMV infection and leishmaniasis infection.

Project Outputs

Olbrich et al 2021. Understanding the interaction between cytomegalovirus and tuberculosis in children: The way forward. Plos Pathogens.