Angiogenesis in Viral Immunoinflammatory

Lesions

Barry T. RouseUniversity of Tennessee

Part 1

The Smokies’ Lost Tribe

“Of course we do not have herpes”

Herpetic Stromal Keratitis

An immunoinflammatory reaction in the eye that appears to represent a Type 1 CD4+ T cell mediated reaction in a tissue, the cornea, that normally lacks a vascular system and has been considered as one site of immunological privilege.

HSV Keratitis in humans

• Most common infectious cause of blindness in USA

• At least 400,000 cases

• About 20% of cases have the immunoinflammatory stromal form

• Requires chronic treatment and may lead to corneal transplantation

Pathogenesis of Stromal Keratitis

• Complex involves multiple humoral and cellular participants

• Neovascularization a major feature

• Principal orchestrators of the lesion are CD4+ T cells of the type 1 phenotype

HSK is caused by CD4+ type 1 T cells but IL-12 expression in the eye prior to HSV infection

diminishes rather than exaggerates the lesions.

-Lee et. Al. 2002

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25

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75

100

0 5 10 15 20

IL-12 DNAvector DNA

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Expression of IL-12 DNA prior to infection inhibits HSK severity and incidence

Inci

den

ce (

%)

Sev

erit

y

Days post infection

How does the IL-12 effect function?

• Antiviral effect via IFN- - No

• Immunosuppression via iNOS - No

• Modulation of immunity - No

• Indirect effect on angiogenesis

-actin

IP-10

IFN-

MIG

IL-10

Gene expression in cornea at day 3 post infection by RT PCR

BALB/c GKO

naive

Virus

+ ve

ctor

Virus

+ IL

-12

Virus

+ ve

ctor

Virus

+ IL

-12

0

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20

An

gio

gen

ic s

cori

ng

0 5 10 15 20

Days post infection

IL-12 DNAIP-10 DNAvector DNA

IL-12 and IP-10 DNA both inhibit ocular angiogenesis

IL-12 DNA effect reversed by anti IP-10 + anti MIG

INTERPRETATION

IL-12 expression causes upregulation via IFN- induction of IP- 10 (and MIG).

These chemokines bind to heparan sulfate and block the angiogenic effect of FGF.

Consequence : inhibited angiogenesis which could be necessary to develop stromal keratitis following virus infection.

• Which molecules are induced in the cornea that can account for HSV-driven neovascularization?

• Is preventing angiogenesis a logical therapeutic goal for herpetic keratitis?

Viruses- neovascularizationVirus Lesion Mechanism

HHV8 Kaposi’s Sarcoma

Encodes multiple angiogenic proteins

HBV Hepatitis Activates HIF-1a that turns on VEGF promoter

HIV Kaposi’s Sarcoma

Tat activates VEGF-R2

HPV Cervical Cancer Increases VEGF via indirect complex mechanism

HSV Herpetic Stromal Keratitis

Mysterious but unraveling

Productive Infection By HSV

• Most host mRNA and protein synthesis rapidly shut down

• A few host proteins are made and secreted. These include IL-1 and IL-6.

• To continue open the Part 2

• from Supercourse-Vet

• htpp://centaur.vri.cz