Macrophage colony-stimulating factor as a weapon against cytomegalovirus

Abstract

Cytomegalovirus (CMV) infection is one of the severe opportunistic infections faced by severely immunocompromised patients. High viral loads cause tissue-invasive disease and expose to death or various indirect effects. Substantial progress was made in monitoring active infection, and antiviral drugs were developed. However, dose-limiting toxicities and genotypic resistance limit therapeutic efficacy and vaccine development is hampered by the complex biology of the virus. In this issue of EMBO Molecular Medicine, Kandalla et al (2023) suggest an innovative strategy using the cytokine macrophage colony-stimulating factor (M-CSF) whose clinical development was left behind two decades ago. By stimulating an endogenous immune defense mechanism, M-CSF promotes viral clearance in a mouse model of hematopoietic stem cell transplantation, without impairing stem cell engraftment. These results reactivate the interest in the potential therapeutic use of this cytokine.

Figure 1. M‐CSF promotes myelopoiesis and a monocyte‐natural killer (NK) cell program to eliminate CMV‐infected cells

(A) M‐CSF was shown to instruct a fraction of hematopoietic stem and progenitor cells (light yellow) in the bone marrow to promote myelopoiesis through a stepwise differentiation process generating monocytes, polymorphonuclear cells (PMN), conventional dendritic cells (cDC), and type I interferon producing plasmacytoid dendritic cells (pDCs), without preventing the generation of other lineages; (B) interaction between monocytes and NK cells: IL5Rα at the surface of monocytes ensures transpresentation of IL‐15 (in green) to NK cells expressing IL15‐Rβ (light beige) and γc (dark beige), promoting NK cell maturation through NKP and their activation. In turn, NK cells may kill virus‐infected cells through cell–cell contact and the release of toxic proteins such as perforin.