Effects of Toll-like receptor stimulation on eosinophilic infiltration in lungs of BALB/c mice immunized with UV-inactivated severe acute respiratory syndrome-related coronavirus vaccine.
Severe acute respiratory syndrome-related coronavirus (SARS-CoV) is an emerging pathogen that causes severe respiratory illness. Whole UV-inactivated SARS-CoV (UV-V), bearing multiple epitopes and proteins, is a candidate vaccine against this virus. However, whole inactivated SARS vaccine that includes nucleocapsid protein is reported to induce eosinophilic infiltration in mouse lungs after challenge with live SARS-CoV. In this study, an ability of Toll-like receptor (TLR) agonists to reduce the side effects of UV-V vaccination in a 6-month-old adult BALB/c mouse model was investigated, using the mouse-passaged Frankfurt 1 isolate of SARS-CoV. Immunization of adult mice with UV-V, with or without alum, resulted in partial protection from lethal doses of SARS-CoV challenge, but extensive eosinophil infiltration in the lungs was observed. In contrast, TLR agonists added to UV-V vaccine, including lipopolysaccharide, poly(U), and poly(I·C) (UV-V+TLR), strikingly reduced excess eosinophilic infiltration in the lungs and induced lower levels of interleukin-4 and -13 and eotaxin in the lungs than UV-V-immunization alone. Additionally, microarray analysis showed that genes associated with chemotaxis, eosinophil migration, eosinophilia, and cell movement and the polarization of Th2 cells were upregulated in UV-V-immunized but not in UV-V+TLR-immunized mice. In particular, CD11b(+) cells in the lungs of UV-V-immunized mice showed the upregulation of genes associated with the induction of eosinophils after challenge. These findings suggest that vaccine-induced eosinophil immunopathology in the lungs upon SARS-CoV infection could be avoided by the TLR agonist adjuvants.


OBJECTIVE
Inactivated whole severe acute respiratory syndrome-related coronavirus (SARS-CoV) vaccines induce neutralizing antibodies in mouse models; however, they also cause increased eosinophilic immunopathology in the lungs upon SARS-CoV challenge. In this study, the ability of adjuvant Toll-like receptor (TLR) agonists to reduce the side effects of UV-inactivated SARS-CoV vaccination in a BALB/c mouse model was tested, using the mouse-passaged Frankfurt 1 isolate of SARS-CoV. We found that TLR stimulation reduced the high level of eosinophilic infiltration that occurred in the lungs of mice immunized with UV-inactivated SARS-CoV. Microarray analysis revealed that genes associated with chemotaxis, eosinophil migration, eosinophilia, and cell movement and the polarization of Th2 cells were upregulated in UV-inactivated SARS-CoV-immunized mice. This study may be helpful for elucidating the pathogenesis underlying eosinophilic infiltration resulting from immunization with inactivated vaccine.
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Naoko
N
Iwata-Yoshikawa
Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.
Akihiko
A
Uda
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Tadaki
T
Suzuki
Department of Immunology, National Institute of Infectious Diseases, Tokyo, Japan.
Yasuko
Y
Tsunetsugu-Yokota
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Yuko
Y
Sato
Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan.
Shigeru
S
Morikawa
Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Masato
M
Tashiro
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Tetsutaro
T
Sata
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
Hideki
H
Hasegawa
Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan nnagata@niid.go.jp.
Noriyo
N
Nagata
D000818:Animals; D018925:Chemokines / Q000032:analysis; D004804:Eosinophils / Q000276:immunology*; D020869:Gene Expression Profiling; D018793:Interleukin-13 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus; D045473:Severe acute respiratory syndrome-related coronavirus / Q000276:immunology*; D045169:Severe Acute Respiratory Syndrome / Q000276:immunology*; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology*; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage / Q000276:immunology*
D018925:Chemokines; D018793:Interleukin-13; D000085064:Receptors, Coronavirus; D011991:Receptors, Virus; D051193:Toll-Like Receptors; D015164:Vaccines, Inactivated; D014765:Viral Vaccines; D015847:Interleukin-4