Nowadays, many people like to keep pet dogs. Dogs live indoors for a long time, lack sunlight and exercise, and have reduced immunity, and are easily infected with diseases. Canine distemper is a highly transmitted disease between dogs. Once infected with canine distemper, the mortality rate will reach more than 80%.
Central nervous system (CNS) infection is the most serious complication of canine distemper, leading to various neurological diseases and often with poor prognosis. Usually, neurological symptoms occur when there are no general signs and are associated with demyelinating lesions. However, not all cases of canine distemper will have neurological symptoms, and there are certain strain differences. For example, the R252 and A75-17 strains currently found mainly cause demyelinated leukoencephalitis, and Snyder Hill mainly causes acute leukoencephalitis.
On the one hand, humoral and cellular immunity are crucial when defending against canine distemper virus infection, and the lack of effective humoral immunity in the early stages can be fatal. On the other hand, the presence of antibodies and the deposition of immune complexes during systemic immune responses have the potential to promote the spread of viruses in CNS endothelial cells. In the article, we introduce in detail how the virus infects the nervous system and the mechanism of demyelination.
01 Viral infection process
Dogs get canine distemper and monoclonal antibodies are generally suitable for several days to get the virus. After the virus infection, it first appears in the phagocytocytes in the upper respiratory tract of the host, and then migrates to lymphoid and hematopoietic tissues (such as spleen, thymus, lymph nodes, bone marrow), causing lymphocytopenia and immunosuppression, and immune suppression provides the basis for secondary bacterial infection. During viral infection, the loss or inadequacy of humoral immunity can promote secondary viremia, which causes epithelial, mesenchymal and central nervous system (CNS) infection. Entering the chronic phase, the immune system gradually recovers.
Figure 1. Mechanisms of CDV infection that lead to immunosuppression: Viral infection and viral N protein/CD32 binding lead to reduced antigen presentation and interfere with the maturation of dendritic and B cells, leading to a significant reduction in plasma cell formation and immunoglobulin production.
02 Viruses invade the nervous system
blood pathway: Virus invades monocytes → passes through the blood-brain barrier → infects the inherent epithelial and endothelial cells in the brain → spreads within the brain with cerebrospinal fluid (CSF) → infects glial cells and neurons.
Other pathways: CDV infects neurons located in the olfactory mucosa → subsequently the virus infects the olfactory bulb along the olfactory nerve fibers → passes to deeper CNS mechanisms.
Viruses recognize and infect cells through cell receptors CD150 and PVRL4, but the expression of these cell receptors in the CNS is very limited. In infected oligodendrocytes, only CDV RNA was detected but no CDV protein was detected, indicating that CDV was only transcribed and not translated in infected oligodendrocytes. This limited infection and the characteristic of viral genes that only transcribe and not translate also confirm the fact that there is no detoxification in the late stage.
03 Mechanism of demyelination lesions
CDV induces microglia activation after infection with CNS → secretes toxin factors (TNF-α, oxygen free radicals) → inhibits the growth of oligodendrocytes and myelin, causing damage to oligodendrocytes and demyelination lesions.
Myelin sheath is a layer of membrane wrapped around the axons of nerve cells. There are three types of glial cells in the central nervous system (CNS): oligodendrocytes, astrocytes, and microglia all participate in the composition of myelin sheath. Among them, abnormal oligodendrocytes lead to demyelination of the central nervous system, causing neuronal damage or mental diseases; microglia are important immune cells in the CNS; astrocytes provide nutrition to nerve cells.
In addition, the bystander mechanism of the interaction between macrophages and antiviral antibodies is an important cause of chronic inflammatory demyelination. During chronic viral infection, the immune response gradually recovers, CD4+ cells infiltrate around the blood vessels, and then a large number of plasma cells are recruited, and intrathecal antibodies are vigorously synthesized. After the CDV antibodies in the blood and cerebrospinal fluid bind to infected cells, they bind to the Fc receptors on adjacent macrophages, inducing the release of a large number of oxygen free radicals, causing the demyelination of oligodendrocytes or myelin sheaths, leading to demyelination, causing neuronal damage or mental diseases.
04 Causes of persistent infection of canine distemper
Virus restriction infection: In oligodendrocytes, the viral genes are constantly replicated, but do not express proteins, which can avoid recognition from the immune system and also trigger new demyelination damage.
Selective transmission of non-lytic cells: After CDV infection, it spreads in the form of non-lytic cells, releasing very limited viruses. In this way, CDV escapes immune surveillance.
Summary
Simply put, early demyelination is mediated by a virus, and late demyelination is mediated by a bystander mechanism involving antigens. After the recovery of the late immune system, humoral immunity is enhanced. Antiviral antibodies that bind infected cells to phagocytes bind to further damage myelin and trigger neurological symptoms. Viral restriction infection greatly reduces viral protein expression and detectable antigen reduction. Insoluble cell-lytic transmission limits viral release, and the immune mechanism that assists the virus to escape the host continues to exist.
Based on this characteristic of canine distemper infection, it is crucial that the prevention and protection of canine distemper provides a good immune defense for dogs in the early stage of canine distemper infection. However, when dogs are in the late stage of canine distemper, the presence of antibodies increases the damage to the nervous system, so it is not recommended to inject monoclonal antibody treatment in the late stage of canine distemper. Humoral immunity runs throughout the entire process of canine distemper infection, and through antibody detection, it helps to formulate and change treatment plans in a timely manner.
Here we remind shit owners to pay attention to the health of their dogs, and prevention is greater than treatment. Don’t wait until the dog has a disease before paying attention. When the disease reaches its late stage, treatment may not necessarily save the life of pets.