Daijiworld Media Network - New Delhi

New Delhi, Sep 13: Rising human rabies cases have renewed attention on how virulent rabies virus infection causes fatal dysfunction of the central nervous system (CNS). New high-resolution single-cell transcriptomic analysis of more than 100,000 CNS cells has shed light on the cellular mechanisms that distinguish lethal encephalitic progression from effective viral clearance.

Using comparative mouse models infected with the highly virulent CVS-11 strain and the attenuated SRV9 strain, researchers identified sharply contrasting immune responses that appear to determine whether infection progresses to fatal neurological disease or is successfully cleared.

Immune breakdown during fatal infection

During fatal rabies infection, resident and infiltrating immune cells in the brain undergo widespread functional changes.

Microglia, the brain’s resident immune cells, move away from their normal homeostatic and neuroprotective states and adopt stress-related, pro-inflammatory and destructive phagocytic characteristics. This shift is accompanied by increased expression of stress-associated genes such as Fkbp5 and Apod, along with elevated levels of inflammatory molecules including interleukin-1 beta and tumour necrosis factor.

The infected brain also shows extensive infiltration of proliferating neutrophils. These cells contribute to severe inflammatory tissue damage through Toll-like receptor and NOD-like receptor pathways.

Natural killer (NK) cells expand into a proliferative population but show markedly reduced functional activity, failing to adequately increase the expression of cytotoxic effector genes.

At the same time, infiltrating T cells exhibit increased exhaustion signatures and higher expression of inhibitory regulators such as Klf2 and Socs3. An expansion of regulatory T cells further suppresses protective immune responses.

Attenuated virus triggers protective response

In contrast, infection with the attenuated viral strain produces a protective neuroimmune environment capable of clearing the virus from the CNS.

In this setting, microglia develop into specialised antigen-presenting cells expressing Cd74 and major histocompatibility complex class II molecules. Tissue-repair programmes involving Spp1 and Tgm2 also become activated.

Infiltrating myeloid cells promote chemokine signalling and coordinated recruitment of immune cells rather than driving destructive inflammation.

NK cells retain strong cytotoxic activity, while both CD4 and CD8 T cells undergo effective effector and memory differentiation without developing the pronounced exhaustion seen during fatal infection.

Researchers found that extensive intercellular communication and balanced immune interactions help preserve neural tissue while supporting effective viral clearance.

The contrasting molecular signatures identified in the study, particularly involving Fkbp5, Apod, Klf2 and Socs3, could provide potential targets for future therapeutic strategies following rabies exposure and may also help guide the development of improved rabies vaccines.

The findings offer new insight into why highly virulent rabies infection can turn the brain’s immune response from a protective mechanism into a driver of lethal neurological disease.