MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

Abstract

MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is in vitro evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency in vivo using murine gammaherpesvirus (MHV-68) infection. MHV-68-infected mice deficient in miR-155 exhibited decreases in GC B cells and Tfh cells. However, the frequencies of spleen cells harboring latent MHV-68 genomes were the same in both miR-155-deficient and wildtype (WT) mice. Similar latent loads were also observed in mixed bone marrow chimeric mice, where B cell-extrinsic effects of miR-155 deficiency were normalized. Interestingly, we observed markedly lower efficiency of reactivation from latency in miR-155-deficient cells, indicating an important role for miR-155 in this process. These in vivo data complement previous in vitro studies and lead to the conclusion that miR-155 is not necessary for the establishment or maintenance of gammaherpesvirus latency but that it does affect reactivation efficiency. IMPORTANCEGammaherpesvirus infection leads to severe disease in immunosuppressed populations. miR-155 has been shown to play important roles in many pathological processes, including tumorigenesis and diseases caused by an overly aggressive immune response. Our work provides valuable in vivo data showing that miR-155 is dispensable for gammaherpesvirus latency but that it is critical for reactivation from latency, which is a crucial step in the viral life cycle. The herpesvirus family is a large and widely distributed family of double-stranded, enveloped DNA viruses. Their anatomical sites of latency and frequency of reactivation vary, resulting in a range of clinical manifestations. A defining feature of this virus family is the ability to establish latent infection within host cells. The gammaherpesviruses distinguish themselves by being lymphotropic, in most cases establishing latency in B cells, where coordinated programs of viral and host gene expression promote B cell differentiation to favor virus latency.Gammaherpesviruses are of clinical interest due to the two human members of this viral subfamily: Epstein-Barr virus (EBV; human herpesvirus 4 [HHV-4]) and Kaposi's sarcoma-associated herpesvirus (KSHV; HHV-8). These viruses are closely associated with the development of malignancies in immunosuppressed populations. EBV was initially recovered from an endemic form of Burkitt's lymphoma, and it has been shown to hijack the B cell differentiation pathway in order to gain access into the long-lived memory B cell compartment (1). Due to the narrow host tropism and seroprevalence of the human gammaherpesviruses, murine gammaherpesvirus (MHV-68) has become a critical model system in which to examine the in vivo immunobiology of...

Expression of Concern: HOXD‐AS1/miR‐130a sponge regulates glioma development by targeting E2F8

“…LncRNAs are potentially implicated in determining glioma development through interaction with different signaling pathways or binding with miRNAs that have a wide range of targets . These in turn allow them to modulate many pathways that are critical to cancer progression, including proliferation, cell death, metastasis, angiogenesis and drug resistance pathways . We performed RNA pull‐down and nuclear–cytoplasmic subcellular location assays and demonstrated that HOXD‐AS1 was more likely to regulate molecular functions through ceRNA manner.…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…As a consequence of impaired Tfh cell generation, loss of miR-155 also leads to aberrant GC responses with reduced frequencies of GC B cells, lower amounts of antigen-specific antibodies, and defective secondary antibody responses [100][101][102][103]. Another interesting finding of this study was that the proliferation of antigen-specific cells in miR-155-deficient mice was impaired between days 3.5 and 4.5 after immunization, but not at earlier time points.…”

“…As a consequence of impaired Tfh cell generation, loss of miR-155 also leads to aberrant GC responses with reduced frequencies of GC B cells, lower amounts of antigen-specific antibodies, and defective secondary antibody responses. [100][101][102][103] In addition to a Tfh cell-intrinsic role of miR-155, several studies confirmed that miR-155 is also highly expressed in GC B cells and controls the GC response upon immunization or viral infection by regulating the size and number of GCs, antibody production, class switch, and affinity maturation in a B cell-intrinsic manner. 94,[103][104][105] Since Tfh cells strongly depend on the interaction with GC B cells for their maintenance, miRNAs therefore also indirectly control Tfh cells through regulation of GC B cells.…”

“…Mechanistically, the repression of Peli1 by miR-155 led to nuclear accumulation of the NF-κB transcription factor c-Rel, which is known to control cell proliferation and CD40L expression, and thus promoted the generation of Tfh cells. In addition to a Tfh cell-intrinsic role of miR-155, several studies confirmed that miR-155 is also highly expressed in GC B cells and controls the GC response upon immunization or viral infection by regulating the size and number of GCs, antibody production, class switch, and affinity maturation in a B cell-intrinsic manner 94,[103][104][105]. 101 This is surprising, since miR-155 is rapidly upregulated in CD4 + T cells within hours after activation, 60 which would point to a function of this miRNA very early in T-helper cell differentiation.…”

Herpesviruses and Their Host Cells: A Successful Liaison

“…, and signaling coreceptors [67,82] Noncoding RNAs (including miRNAs) [41,42,48] Proteins interacting with oriLyts [51] Interferons and other cytokines [30,[32][33][34] Sensors of viral infection [23,83,84] Cell cycle proteins [62,85,86] Proteins regulating apoptosis [87][88][89][90] Transcription factors [91] DNA damage response proteins [5] Proteins involved in epigenetic gene regulation including chromatin assembly, histone modifications[ 3 _ T D $ D I F F ] , and DNA methylation [21][22][23][24][25][26][27][28]63,[92][93][94][95][96][97][98] Autophagy and xenophagy [99][100][101] Ubiquitination and NEDDylation [102][103][104][105] Chaperones [65] Post-translational modification proteins …”