TY - JOUR
T1 - Transcutaneous immunization using SLA or rLACK skews the immune response towards a Th1 profile but fails to protect BALB/c mice against a Leishmania major challenge
AU - Lakhal-Naouar, Ines
AU - Koles, Nancy
AU - Rao, Mangala
AU - Morrison, Elaine B.
AU - Childs, John M.
AU - Alving, Carl R.
AU - Aronson, Naomi E.
N1 - Publisher Copyright:
© 2018 The Authors
PY - 2019/1/14
Y1 - 2019/1/14
N2 - Leishmaniasis is an expanding health threat worldwide complicated by the absence of an effective vaccine. We investigated transcutaneous immunization (TCI) as a needle-free immunization route which exploits the abundance of antigen presenting cells in the skin to induce both mucosal and systemic immunity. Leishmania (L.) major soluble antigens (SLA) or recombinant Leishmania homolog of receptors for activated C-kinase (rLACK) antigens were delivered transcutaneously together with cholera toxin (CT), to BALB/c mice. Mice were immunized at weeks 1, 4, and 7 with PBS, CT, SLA/CT or rLACK/CT. Two weeks after the final boost, antigen-specific IgG titers, IFN-γ ELISpot, and cytokine levels were assessed in half of the mice and the remainder were challenged with an intradermal (ear) injection of 5 × 104 L. major metacyclic parasites. Mice were monitored weekly and sacrificed after 7 weeks to assess the parasite burden and to study the ear lesion immunohistopathology. Our results show that TCI with SLA or rLACK yielded high levels of anti-SLA, anti-rLACK and anti-CT IgG antibodies. A Th1-type of immune response was demonstrated with a high frequency of IFN-γ secreting cells, high levels of IFN-γ production, and lower levels of IL-10 resulting in a high IFN-γ/IL-10 ratio in mice immunized with SLA/CT or rLACK/CT. After parasite challenge, rLACK immunization was not associated with protection. In addition, SLA/CT immunized mice had larger ear lesions and an increased parasite load in the ear. Immunohistochemistry of ear biopsies stained for nitric oxide synthase revealed that staining intensity was diminished in the SLA/CT group compared to the control group. This finding suggested that less parasite killing occurred at the site of the infection. In conclusion, despite a strong Th1 type profile induced by TCI, exacerbation of infection occurred after challenge with L. major. This also correlated with low induction of nitric oxide.
AB - Leishmaniasis is an expanding health threat worldwide complicated by the absence of an effective vaccine. We investigated transcutaneous immunization (TCI) as a needle-free immunization route which exploits the abundance of antigen presenting cells in the skin to induce both mucosal and systemic immunity. Leishmania (L.) major soluble antigens (SLA) or recombinant Leishmania homolog of receptors for activated C-kinase (rLACK) antigens were delivered transcutaneously together with cholera toxin (CT), to BALB/c mice. Mice were immunized at weeks 1, 4, and 7 with PBS, CT, SLA/CT or rLACK/CT. Two weeks after the final boost, antigen-specific IgG titers, IFN-γ ELISpot, and cytokine levels were assessed in half of the mice and the remainder were challenged with an intradermal (ear) injection of 5 × 104 L. major metacyclic parasites. Mice were monitored weekly and sacrificed after 7 weeks to assess the parasite burden and to study the ear lesion immunohistopathology. Our results show that TCI with SLA or rLACK yielded high levels of anti-SLA, anti-rLACK and anti-CT IgG antibodies. A Th1-type of immune response was demonstrated with a high frequency of IFN-γ secreting cells, high levels of IFN-γ production, and lower levels of IL-10 resulting in a high IFN-γ/IL-10 ratio in mice immunized with SLA/CT or rLACK/CT. After parasite challenge, rLACK immunization was not associated with protection. In addition, SLA/CT immunized mice had larger ear lesions and an increased parasite load in the ear. Immunohistochemistry of ear biopsies stained for nitric oxide synthase revealed that staining intensity was diminished in the SLA/CT group compared to the control group. This finding suggested that less parasite killing occurred at the site of the infection. In conclusion, despite a strong Th1 type profile induced by TCI, exacerbation of infection occurred after challenge with L. major. This also correlated with low induction of nitric oxide.
KW - BALB/c
KW - Leishmania
KW - SLA
KW - Th1
KW - Transcutaneous immunization
KW - rLACK
UR - http://www.scopus.com/inward/record.url?scp=85057800099&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2018.11.052
DO - 10.1016/j.vaccine.2018.11.052
M3 - Article
C2 - 30528328
AN - SCOPUS:85057800099
SN - 0264-410X
VL - 37
SP - 516
EP - 523
JO - Vaccine
JF - Vaccine
IS - 3
ER -