Human rhinovirus 16 infection of human macrophages disrupts Arpin expression impairing macrophage internalization: a potential link to exacerbation in chronic obstructive pulmonary disease?

Abstract

Alveolar macrophages (AM) are crucial to COPD pathogenesis. Evidence suggests they have defective internalisation mechanisms which could drive disease exacerbations where human rhinovirus (HRV) is isolated. We hypothesised HRV infection of macrophages could impair their internalisation functions.

AM or monocyte derived macrophages (MDM) were challenged with HRV16 and then with various triggers and internalisation assessed. Changes to the actin cytoskeleton following HRV16 infection and following particle internalisation were assessed by microscopy.

AM or MDM challenged with HRV16 demonstrated deficient internalisation towards multiple triggers. HRV16 exaggerated deficient internalisation in COPD AM. HRV16 altered the actin cytoskeleton in macrophages driving persistence of actin around internalised particles. Screening for actin regulators affected by HRV16 identified Arpin, a negative Arp2/3 regulator to be significantly decreased after infection. Re-expression of Arpin after infection restored internalisation defects. Further, Arpin depletion impaired internalisation in a similar manner as HRV16 with internalisation stalling at the same point with significantly reduced bacterial uptake. These results confirm that HRV16 targets Arpin in macrophages to impair particle internalisation.

Our results demonstrate HRV16 impairs various macrophage internalisation pathways by targeting Arpin. Hence, HRV16 can hijack macrophage functions and an important phagocytic regulator possibly explaining why COPD patients show secondary bacterial infection post virus infection with increased bacterial numbers.