Modulation of HSV infection
Toll-like receptor 2 (TLR2) has been found to mediate certain effects of HSV infection, particularly in neonates. Compounds that decrease TLR2 expression or activity are useful for ameliorating such deleterious effects.
1. A method of reducing toll-like receptor 2 (TLR2) mediated inflammation associated with herpes simplex virus (HSV) infection in a subject in need thereof, the method comprising:
identifying a subject with HSV who has or is at risk for developing TLR2 mediated inflammation associated with HSV; and
administering to the subject a therapeutically effective amount of a TLR2 antisense nucleic acid or small interfering RNA (siRNA) for a period of time and under conditions sufficient to promote a decrease in the expression of TLR2 mRNA, wherein the antisense nucleic acid or siRNA specifically targets all or a portion of human TLR2 mRNA (SEQ ID NO:1) and promotes a decrease in the expression of TLR2 mRNA upon binding thereto, thereby reducing TLR2 mediated inflammation associated with HSV infection in the subject.
2. The method of claim 1 , wherein the subject is a human.
3. The method of claim 1 , wherein the subject is a child or an adult.
4. The method of claim 1 , wherein the subject is a neonate.
5. The method of claim 1 , wherein the subject has at least one symptom of encephalopathy.
6. The method of claim 5 , wherein the method ameliorates a symptom of encephalopathy in the subject.
7. The method of claim 6 , wherein the symptom of encephalopathy is selected from the group consisting of malaise, fever, headache, nausea, lethargy, confusion, delirium, seizures, aphasia, cranial nerve deficits, and hemiparesis.
8. The method of claim 5 , wherein the subject is a neonate and the method ameliorates a symptom of Toxoplasmosis, Other Agents, Rubella, Cytomegalovirus, Herpes Simplex (TORCH) syndrome in the subject.
9. The method of claim 8 , wherein the symptom is selected from the group consisting of fever, difficulties feeding, hepatosplenomegaly, cutaneous manifestations, hearing impairment, and abnormalities of the eyes.
10. The method of claim 9 , wherein the cutaneous manifestations are selected from the group consisting of petechiae, purpura, jaundice, and dermal erythropoiesis.
11. The method of claim 5 , wherein the method ameliorates a symptom selected from the group consisting of blisters on the cornea, skin or mucous membranes, itching, burning, soreness, skin ulcers, enlarged and/or painful lymph nodes in the groin, blurred vision, headache, fever, burning during urination, and general malaise in the subject.
12. The method of claim 1 , wherein the HSV is HSV-1 or HSV-2.
13. The method of claim 1 , wherein the antisense nucleic acid or siRNA is a double stranded siRNA that specifically targets human TLR2 mRNA (SEQ ID NO:1), wherein one of the strands comprises 16 to 30 contiguous nucleotides of SEQ ID NO:1, the other strand is complementary to the first strand, and the siRNA reduces human TLR2 mRNA expression in a cell.
14. The method of claim 13 , wherein the antisense nucleic acid or siRNA is an antisense nucleic acid comprising at least 20 contiguous nucleotides of SEQ ID NO:1 or the complement thereof that reduces human TLR2 mRNA expression in a cell.
15. The method of claim 1 , wherein the subject at risk for developing TLR2 mediated inflammation associated with HSV is infected with HSV and does not have TLR2 inflammation.
16. A method of reducing herpes simplex virus (HSV)-dependent expression of IL-6, NF-κB, or both IL-6 and NF-κB, in a human cell, the method comprising:
obtaining a cell comprising HSV; and
contacting the cell with a therapeutically effective amount of a TLR2 antisense nucleic acid or siRNA that specifically targets human TLR2 mRNA (SEQ ID NO:1) and thereby decreases human TLR2 mRNA expression, thereby reducing HSV-dependent expression of IL-6 or NF-κB, or both IL-6 and NF-κB in the cell.