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Chronic Lymphocytic Choriomeningitis Infection Causes Susceptibility to Mousepox and Impairs Natural Killer Cell
Pedro Alves-Peixoto1,2,3, Maria Férez1, Cory J Knudson1
1Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Abstract:
Chronic viral infections. like those of humans with cytomegalovirus, human immunodeficiency virus (even when under antiretroviral therapy), and hepatitis C virus or those of mice with lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13), result in immune dysfunction that predisposes the host to severe infections with unrelated pathogens. It is known that C57BL/6 (B6) mice are resistant to mousepox, a lethal disease caused by the orthopoxvirus ectromelia virus (ECTV), and that this resistance requires natural killer (NK) cells and other immune cells. We show that most B6 mice chronically infected with CL13 succumb to mousepox but that most of those that recovered from acute infection with the LCMV Armstrong (Arm) strain survive. We also show that B6 mice chronically infected with CL13 and those that recovered from Arm infection have a reduced frequency and a reduced number of NK cells. However, at steady state, NK cells in mice that have recovered from Arm infection mature normally and, in response to ECTV, get activated, become more mature, proliferate, and increase their cytotoxicity in vivo Conversely, in mice chronically infected with CL13, NK cells are immature and residually activated, and following ECTV infection, they do not mature, proliferate, or increase their cytotoxicity. Given the well-established importance of NK cells in resistance to mousepox, these data suggest that the NK cell dysfunction caused by CL13 persistence may contribute to the susceptibility of CL13-infected mice to mousepox. Whether chronic infections similarly affect NK cells in humans should be explored.IMPORTANCE Infection of adult mice with the clone 13 (CL13) strain of lymphocytic choriomeningitis virus (LCMV) is extensively used as a model of chronic infection. In this paper, we show that mice chronically infected with CL13 succumb to challenge with ectromelia virus (ECTV; the agent of mousepox) and that natural killer (NK) cells in CL13-infected mice are reduced in numbers and have an immature and partially activated phenotype but do respond to ECTV. These data may provide additional clues why humans chronically infected with certain pathogens are less resistant to viral diseases.
Insights
Chronic lymphocytic choriomeningitis virus (LCMV) infection impairs natural killer (NK) cells, increasing susceptibility to secondary infections like mousepox. Recovery from acute LCMV infection allows for normal NK cell function and survival against mousepox.
Area of Science:
- Immunology
- Virology
- Infectious Diseases
Background:
- Chronic viral infections, including human cytomegalovirus, HIV, and hepatitis C, lead to immune dysfunction and increased susceptibility to other infections.
- Natural killer (NK) cells are crucial for resistance to mousepox, a lethal disease caused by ectromelia virus (ECTV).
- Lymphocytic choriomeningitis virus (LCMV) clone 13 (CL13) is a model for chronic viral infection, while the Armstrong (Arm) strain causes acute infection.
Purpose of the Study:
- To investigate the impact of chronic LCMV CL13 infection on NK cell function and susceptibility to secondary infections.
- To compare the effects of chronic LCMV CL13 infection versus recovery from acute LCMV Arm infection on NK cell responses.
- To determine if NK cell dysfunction contributes to increased susceptibility to mousepox in chronically infected mice.
Main Methods:
- Mice (C57BL/6) were infected with LCMV CL13 (chronic) or LCMV Arm (acute).
- Mice were subsequently challenged with ectromelia virus (ECTV) to model mousepox.
- NK cell frequency, number, maturation status, activation phenotype, and cytotoxic activity were analyzed in infected and recovered mice.
Main Results:
- Mice chronically infected with LCMV CL13 succumbed to ECTV challenge, unlike mice that recovered from LCMV Arm infection.
- Both chronically infected and recovered mice showed reduced NK cell numbers.
- NK cells from LCMV CL13-infected mice were immature and partially activated, failing to mature, proliferate, or increase cytotoxicity upon ECTV challenge. In contrast, NK cells from LCMV Arm-recovered mice matured, activated, proliferated, and enhanced cytotoxicity against ECTV.
Conclusions:
- Chronic LCMV CL13 infection causes NK cell dysfunction, characterized by immaturity and impaired responsiveness.
- This NK cell dysfunction likely contributes to the increased susceptibility of chronically infected mice to secondary pathogens like ECTV.
- Further research is warranted to explore if chronic viral infections similarly impact NK cells in humans.
