Oskar Olsson (a,b) [Corresponding author: oskar.olsson@med.lu.se] , Fregenet Tesfaye (a,c), Rolf Søkilde (d), Jolanta Mazurek (e), Markos Abebe (c), Abraham Aseffa (c), Sten Skogmar (a,b), Taye Tolera Balcha (a), Carlos Rovira (d), Per Björkman (a,b), Marianne Jansson (f)

Affiliates

(a)Clinical Infection Medicine, Department of Translational Medicine, Lund University, Malmö, Sweden, (b)Department of Infectious Diseases, Skåne University Hospital, (c)Armauer Hansen Research Institute, Addis Ababa, Ethiopia, (d)Breastca-genetics, Cancer and non-coding RNA, Lund University Cancer Centre, Lund University, Lund Sweden, (e)Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (f)Division of Medical Microbiology, Department of Laboratory Medicine, Lund U niversity, Lund, Sweden

Abstract

Background
HIV infection affects the course of tuberculosis (TB), and HIV and Mycobacterium tuberculosis (Mtb) synergize in disease progression through complex immunological interplay.
Aim
To gain further understanding of these mechanisms, we compared the microRNA (miRNA) and small nucleolar RNA (snoRNA) expression in whole blood of individuals with active TB, with and without HIV coinfection (HIV+/TB+ and HIV-/TB+), and HIV and TB-negative individuals (HIV-/TB-).
Methods
Whole blood was first analyzed for snoRNA and miRNA expression using microarray, and a subset of differentially expressed RNA were further explored using qPCR. Samples taken after treatment were also analyzed. Patterns of expression were explored with principal component analysis and hierarchical clustering.
Results
We found that 218 miRNAs were differentially expressed between HIV+/TB+ and HIV-/TB+, while no statistically significant difference in snoRNA expression was observed between these groups (Figure 1). In contrast, both miRNA (n=179) and snoRNA (n=103) expression patterns were significantly altered in HIV+/TB+ individuals compared to those of the HIV-/TB- controls. Of note, 26 of these snoRNAs were also significantly altered between the HIV-/TB+ and HIV-/TB- groups. This pattern of difference in miRNA expression with respect to HIV infection and of snoRNA expression with respect to TB was also evident in a principal component analysis of all RNA (Figure 2). Hierarchical clustering analysis with the 20 most differentially expressed RNA showed uniform clustering to each group, with one exception. Normalization towards the miRNA and snoRNA expression patterns of the HIV-/TB- control group was noted during anti-TB and antiretroviral treatment in HIV+/TB+ participants.
Conclusion
In summary, these results show that HIV coinfection influences miRNA expression in active TB. In contrast, snoRNA expression patterns differ between individuals with and without active TB, independently of HIV coinfection status. Moreover, in coinfected individuals, therapy-induced control of HIV replication and clearance of Mtb appears to normalize the expression of some small non-coding RNA. These findings suggest that dysregulation of miRNA is a mechanism by which HIV may modify immunity against TB, while active TB alters snoRNA expression. Improved understanding of how regulation of sncRNA expression influences the disease course in coinfected individuals may have implications for diagnostics, risk stratification, and host-directed therapy. Here, we propose a novel mechanism by which HIV alters the immune response to TB.